Naphthalene derivative

ABSTRACT

Naphthalene derivatives represented by formula  I!: ##STR1## (wherein A is a hydrogen atom, a hydroxy group, a C 7  -C 11  aralkyloxy group, or an alkoxy group composed of an oxy group and a C 1  -C 12  aliphatic or alicyclic, saturated or unsaturated hydrocarbon group where the allyl may be substituted with a C 6  -C 10  allyloxy group; Q represents O, S, CH 2 , O--CH 2 , S--CH 2 , CO, or CHOR 1  ; L represents CO, CR 2  R 3  CO, CH 2  CH 2  CO, or CH═CHCO; D represents a hydrogen atom, NO 2 , NH 2 , CO 2  R 4 , or a group having the following formula  II!: ##STR2## (wherein G represents. a hydrogen atom, OH, SO 2  NH 2 , CO 2  R 6 , CN, or a tetrazol-5-yl group); E represents a hydrogen atom, OH, SO 2  NH 2 , CO 2  R 5 , CN, or a tetrazol-5-yl group; M represents a hydrogen atom, a C 1  -C 4  lower alkyl group, a nitro group, or a halogen atom; and R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are, independently each other, a hydrogen atom or a C 1  -C 4  lower alkyl group); 
     pharmacologically acceptable salts thereof, or pharmacologically acceptable solvates thereof, which have, for example, an inhibitory effect on the production of IgE antibodies, and will be useful for prophylaxis and/or treatment of allergic diseases.

This application is a 371 of PCT/JP95/01035, filed May 30, 1995.

TECHNICAL FIELD

The present invention relates to new naphthalene derivatives, their pharmacologically acceptable salts or their pharmacologically acceptable solvates, the pharmaceutical compositions containing them, and the application thereof as drugs. More particularly, the present invention relates to new naphthalene derivatives having a naphthalene moiety and two benzene moieties at the same time or their pharmacologically acceptable salts, or their pharmacologically acceptable solvates, the pharmaceutical compositions containing them, and the application thereof as drugs. Furthermore particularly, the present invention relates to the new naphthalene derivatives which, owing to a feature of inhibiting the production of IgE antibodies, is useful as a drug for prophylaxis and/or treatment of allergic diseases, or is useful as a drug for prophylaxis and/or treatment of the diseases caused by enhanced production or activity of TF (tissue factor), and their pharmacologically acceptable salts, or their pharmacologically acceptable solvates.

BACKGROUND ART

It has been known that various chemical mediators released from mast cells are deeply involved in the production of allergic diseases represented by asthma and atopic dermatitis, and that the allergic reaction arises as a result of binding of the Fc region of IgE antibodies with their receptors on the membranes of those cells. Indeed, it has been also known that the serum or tissue concentration of IgE antibodies of the patient with an allergic disease is considerably higher an than that of normal persons. Furthermore, the patient with an allergic disease has been known to show a maintained production of interleukin 4 (IL-4) which plays an important role in the production of IgE antibodies. Accordingly, if a drug were discovered that could inhibit the production of IgE antibodies, it would be effective for prophylaxis and/or treatment of allergic diseases. However, what is now used for the treatment of allergic diseases mainly consists of drugs blocking the receptor of histamine which is one of chemical mediators, or drugs suppressing the release of chemical mediators from their productive cells, and drugs that might inhibit the production of IgE antibodies have never been used for the treatment of allergic diseases. If a new drug were discovered that could inhibit the production of IgE antibodies, it would be useful as a more fundamental drug for prophylaxis and/or treatment of allergic diseases, because it would intercept allergic reactions at an earlier stage than is possible with the conventional drugs that interfere with the release of chemical mediators from their productive cells.

TF (tissue factor) is a complex composed of lipids and glycoproteins localized in the membrane fraction from tissues and cells, and recognized widely over the living body especially in brain, lungs, placenta, kidneys, etc. In addition, vascular endothelial cells, monocytes and/or macrophages, when stimulated from outside, are induced to produce TF, and express it on the surface of their cell membranes.

This TF is practically an initiator of extrinsic coagulation pathway, and is deeply involved in hemostasis/coagulation. More precisely, TF forms a complex with factor VII to activate factor VII, and the resulting TF-VIIa complex contributes to the activation of factors IX and X. Further, because TF is expressed/produced by macrophages as mentioned above, it has been thought that it is involved in biophylaxis including the immune system.

When a tissue is injured in trauma, burns, a variety of operations, or in lesions such as malignant tumors, fulminant hepatitis, sepsis and the like, TF is released into blood stream, which may activate the extrinsic coagulation pathway so much as to cause various disorders. DIC (disseminated intravascular coagulation) is known as one of such disorders. Further, during infection, delayed immune response, various rejection reactions subsequent to tissue transplantation, glomerular nephritis, viral hepatitis, etc., production of TF in vascular endothelial cells, monocytes, and/or macrophages is enhanced to cause thrombosis. Furthermore, thrombin which is located downstream of the extrinsic coagulation pathway can also act as a stimulant of proliferation of smooth muscles. Therefore, increased activity of TF may result in diseases related with thickened endothelium such as arteriosclerosis or restenosis.

Even if an injury is inflicted on an avascular tissue, it causes enhanced production of TF in the affected cells, which may lead to various disorders. One of such disorders is opacification after the insertion of an artificial crystalline lens for the treatment of cataract (Japanese Patent TOKKAIHEI (Unexamined) No. 5-271068 and Takahashi, J. Jap. Opthalmol. Soc., 97:792-799, 1993).

From above it is obvious that if a drug were found that could suppress the production or activity of TF, it would be also quite effective for prophylaxis/treatment of the disorders closely related with enhanced production/activity of TF.

Prior arts related with the compounds of this invention include the following.

Japanese Patent TOKKAIHEI (Unexamined) No. 1-287066 showed that the compound having a naphthalene moiety and an anthranilic acid moiety at the same time such as N-(2-naphthoyl) anthranilic acid has an antiallergic activity or an inhibitory activity of 5-lipoxygenase. However, the compound described in this reference is characterized with a structure wherein a two-ring aromatic derivative which has been substituted with hydroxy or alkoxy groups is directly combined with an anthranilic acid moiety via amide bond. Further, the reference did not mention anything whether the compound has an inhibitory effect on the production of IgE antibodies.

Similarly, Japanese Patent TOKKAISHO (Unexamined) No. 63-270634 demonstrated that the compound which has a naphthalene moiety and an anthranilic acid moiety at the same time can inhibit the activity of lipoxygenase and have an anti-SRS-A activity. However, in the compound described above, a naphthalene moiety is connected to an anthranilic acid moiety via an alkyl aliphatic. Further, the reference gave no mention whether the compound inhibits the production of IgE antibodies.

Furthermore, Japanese Patent TOKKAIHEI (Unexamined) No. 1-106818 and PCT WO 90/12001 describes the compound having a naphthalene moiety is capable of suppressing allergy reactions and of inhibiting the production of IgE antibodies. However, those compounds described in the two references have the following characteristics: the former must have a cyclopropane structure, and the latter must have substitutable groups in the naphthalene ring such as hydroxy groups.

According to an article (Eur. J. Med. Chem. 26:159-166 (1991)), it was reported that a group of compounds having naphthalene moiety is capable of inhibiting the activity of lipoxygenase, and that a certain compound comprising a naphthalene moiety and a 2-hydroxyaniline amide structure is mentioned. However, in this compound, a naphthalene moiety is connected to a 2-hydroxyaniline amide structure via an alkyl aliphatic. Furthermore, that article gave no mention whether the compound has an inhibitory effect on the production of IgE antibodies.

Further, in EP-102325-A, there was a description of a compound wherein a benzene moiety is linked via a sulfone group to a naphthalene moiety, and to the benzene moiety another benzene moiety is linked via amide bond. However, the present specification described herein did not disclose the compound where a naphthalene moiety was linked to a benzene moiety via a sulfone group. Further the latter benzene moiety linked to the former benzene via amide has a sulfonic acid substituent. Therefore, the compound in question is obviously different from the compound in this invention. Furthermore, the reference does not give any mention about inhibitory effects of that compound on the production of IgE antibodies.

In another article (Helv. Chem. Acta 39:1892-1899 (1956)), it was reported a compound where a benzene moiety was linked to a naphthalene moiety via a carbonyl group, and then another benzene was linked to above benzene moiety via amide bond. However, as regards the compound described in this article, the former benzene moiety linked to the naphthalene moiety via a carbonyl group has a nitro substituent at the meta-position of the carbonyl group, and the second benzene moiety linked to above benzene moiety via amide bond has a dimethylamino substituent. In short, the compound in the article is obviously different from the compound in this invention is going to present. Further, the article did not mention any inhibitory effects of the compound on the production of IgE antibodies.

Furthermore, neither articles nor references mentioned heretofore described whether the compounds have any inhibitory effects on TF activities.

Japanese Patents TOKKAIHEI Nos. 3-215421 and 5-271068 disclosed that certain compounds interfere with the activity of TF. However, these compounds have a naphthalene moiety, a cyclopropane moiety, and an anthranilic acid moiety at the same time, thus being quite different in structure from the compound this invention is going to present.

It has been known that the compounds interfering with the activity of TF include Vitamin A (Horie et al., Japanese Patent TOKKAIHEI No. 4-290818), phospholipid derivatives (U.S. Pat. No. 3,264,378), and PLA₂ inhibitors such as 4-bromophenacyl bromide or quinacrine (BBRC 119:179-184, (1984)). However, these compounds have no similarities in their structure to the compound this invention is going to present.

With these prior arts as a background, the present inventors had studied to provide new naphthalene derivatives useful as a pharmaceutical product, and succeeded in providing the compounds of this invention.

DISCLOSURE OF THE INVENTION

The present invention provides naphthalene derivatives having the following formula I!: ##STR3## (wherein A represents a hydrogen atom, a hydroxy group, a C₇ -C₁₁ aralkyl oxy group, or an alkoxy group composed of an oxy group and a C₁ -C₁₂ aliphatic or alicyclic, saturated or unsaturated hydrocarbon group where the alkyl may be substituted with a C₆ -C₁₀ aryloxy group; Q represents O, S, CH₂, O--CH₂, S--CH₂, CO, or CHOR¹ ; L represents CO, CR² R³ CO, CH₂ CH₂ CO, or CH═CHCO; D represents a hydrogen atom, NO₂, NH₂, CO₂ R⁴, or a group having the following formula II!: ##STR4## (wherein G represents a hydrogen atom, OH, SO₂ NH₂, CO₂ R⁶, CN, or a tetrazol-5-yl group); E represents a hydrogen atom, OH, SO₂ NH₂, CO₂ R⁵, CN, or a tetrazol-5-yl group; M represents a hydrogen atom, a C₁ -C₄ lower alkyl group, a nitro group, or a halogen atom; and R¹, R², R³, R⁴, R⁵ and R⁶, independently each other, represent a hydrogen atom or a C₁ -C₄ lower alkyl group); pharmacologically acceptable salts thereof and pharmacologically acceptable solvates thereof; pharmaceutical compositions comprising the naphthalene derivatives, pharmacologically acceptable salts thereof, or pharmacologically acceptable solvates thereof as an active ingredient and a pharmaceutically acceptable carrier; drugs effective for propylaxis and/or treatment of allergic diseases, comprising the naphthalene derivatives, pharmacologically acceptable salts thereof, or pharmacologically acceptable solvates thereof as an active ingredient, and characterized by having an inhibitory activity on the production of IgE antibodies; and drugs effective for propylaxis and/or treatment of diseases caused by enhanced production or activity of TF, comprising the naphthalene derivatives, pharmacologically acceptable salts thereof, or pharmacologically acceptable solvates thereof as an active ingredient.

BEST EMBODIMENT OF THE INVENTION

In formula I!, M represents a hydrogen atom, a C₁ -C₄ lower alkyl group, a nitro group or a halogen atom. The lower alkyl group includes methyl, ethyl, (n-, i-) propyl and (n-, i-, t-) butyl group, and the halogen atom includes fluorine, chlorine and bromine atoms. Among these, hydrogen atom, methyl group, ethyl group, nitro group, fluorine atom or chlorine atom is preferred as F, particularly hydrogen atom is most preferred.

In formula I!, E represents OH, SO₂ NH₂, CO₂ R⁵, CN or a tetrazol-5-yl group. Among these, CO₂ R⁵ or a tetrazol-5-yl is preferred as E. Here R⁵ represents a hydrogen atom or a C₁ -C₄ lower alkyl group. The lower alkyl group includes methyl, ethyl, (n-, i-) propyl and (n-, i-, t-) butyl group. Among these, hydrogen atom, a methyl group or ethyl group is particularly preferred as R⁵.

In formula I!, D represents a hydrogen atom, NO₂, NH₂, CO₂ R⁴ (R⁴ represents a hydrogen atom or a C₁ -C₄ lower alkyl group), or a group represented by formula II! (where G represents a hydrogen atom, OH, SO₂ NH₂, CO₂ R⁶ (R⁶ represents a hydrogen atom or a C₁ -C₄ lower alkyl group), CN, or a tetrazol-5-yl group). Among these, a hydrogen atom, NO₂, NH₂, or the group represented by formula II! is preferred as D. As G, a hydrogen atom or CO₂ R⁶ is preferred. Further, R⁴ and R⁶ independently represent a hydrogen atom or a C₁ -C₄ lower alkyl group. The lower alkyl group includes methyl, ethyl, (n-, i-) propyl and a (n-, i-, t-) butyl group. As R⁴ and R⁶, independently each other, a hydrogen atom, a methyl group or ethyl group is preferably mentioned.

In formula I!, A represents a hydrogen atom, a hydroxy group, a C₇ -C₁₁ aralkyl oxy group, or an alkoxy group composed of an oxy group and a C₁ -C₁₂ aliphatic or alicyclic, saturated or unsaturated hydrocarbon group where the alkyl may be substituted with a C₆ -C₁₀ aryloxy group.

The compounds represented by A include, for example, hydrogen atom, hydroxy group, methoxy group, ethoxy group, (n-, i-) propyloxy group, (n-, i-, t-) butoxy group, n-pentyloxy group, n-hexyloxy group, n-octyloxy group, n-decyloxy group, n-dodecyloxy group, cyclopropyloxy group, cyclopropylmethyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group, allyloxy group, crotyloxy group, 3-butenyloxy group, 4-pentenyloxy group, 5-hexenyloxy group, 7-octenyloxy group, geranyloxy group, 2-phenoxyethoxy group, 3-phenoxypropyloxy group, 4-phenoxybutoxy group, benzyloxy group, 2-phenylethoxy group, 3-phenylpropyloxy group, 1-naphtylmethyloxy group, 2-naphtylmethyloxy group, etc. Among these, a hydrogen atom; a hydroxy group; a benzyloxy group, a phenylpropyloxy group, or a naphtylmethyloxy group; or an alkoxy group composed of an oxy group and a C₁ -C₁₂ aliphatic or alicyclic saturated hydrocarbon group where the alkyl may be substituted by a phenyloxy group or an alkoxy group composed of an oxy group and a C₃ -C₁₀ aliphatic unsaturated hydrocarbon group; such as hydrogen atom, hydroxy group, methoxy group, ethoxy group, (n-, i-) propyloxy group, (n-, i-, t-) butoxy group, n-hexyloxy group, n-octyloxy group, n-decyloxy group, n-dodecyloxy group, cyclopropylmethyloxy group, cyclohexyloxy group, allyloxy group, 4-pentenyloxy group, geranyloxy group, 4-phenoxybutoxy group, benzyloxy group, 3-phenylpropyloxy group, 1- naphtylmethyloxy group, 2-naphtylmethyloxy group can be mentioned as preferred compounds. More specifically, a hydrogen atom; a hydroxy group; an alkoxy group composed of an oxy group and a C₁ -C₈ aliphatic or alicyclic saturated hydrocarbon group which can be substituted by a phenyloxy group such as methoxy group, t-butoxy group, n-octyloxy group, 4-phenoxybutoxy group, cyclohexyloxy group; or an alkoxy group composed of an oxy group and a C₃ -C₁₀ aliphatic unsaturated hydrocarbon group such as allyloxy group, 4-pentenyloxy group, or geranyloxy group; benzyloxy group, 3-phenylpropyloxy group, or 2-naphtylmethyloxy group is most preferred.

In formula I!, Q represents O, S, CH₂, O--CH₂, S--CH₂, CO or CHOR¹ (R¹ represents a hydrogen atom or a C₁ -C₄ lower alkyl group). Among these, Q should preferably be O, S, CH₂, O--CH₂, S--CH₂, or CHOR¹. More specifically, O, S, CH₂ or CHOR¹ is preferred, and O is preferred best of all. R¹ represents a hydrogen atom or a C₁ -C₄ lower alkyl group. The lower alkyl group includes methyl group, ethyl group, (n-, i-) propyl group, (n-, i-, t-) butyl group, etc. Among these, hydrogen atom, methyl group or ethyl group should be preferred as R¹.

In formula I!, L represents CO, CR² R³ CO (R² and R³ are hydrogen atom or C₁ -C₄ lower alkyl group independently from each other), CH₂ CH₂ CO, or CH═CHCO. Among these, CO, CR² R³ CO or CH═CHCO is preferred as L. Particularly, CO or CR² R³ CO are preferred.

In preferred embodiments, R² and R³ independently each other represent hydrogen atom or C₁ -C₄ lower alkyl group. The lower alkyl group includes methyl group, ethyl group, (n-, i-) propyl group, (n-, i-, t-) butyl group, etc., and among these, hydrogen atom, methyl group, or ethyl group is preferred independently as R² and R³. In the best preferred combinations, both R² and R³ represent hydrogen atom, or in preferred combinations one of them consists of hydrogen atom and the other of C₁ -C₄ lower alkyl group (particularly methyl or ethyl group).

In formula I!, the preferred combinations of E and D include CO₂ R⁵ or tetrazol-5-yl group as E, and hydrogen atom, NO₂, NH₂, or a group represented by formula II! as D. Among these, a combination of CO₂ R⁵ as E, and hydrogen atom or NO₂ as D is preferred. In these cases, R⁵ represents hydrogen atom or C₁ -C₄ lower alkyl group, particularly hydrogen atom, methyl group or ethyl group. As for the groups included in formula II!, G represents a hydrogen atom or CO₂ R⁶, and R⁶ represents a hydrogen atom or a C₁ -C₄ lower alkyl group, particularly a hydrogen atom, a methyl group or ethyl group.

In formula I!, the preferred combinations of Q and L include:

(1) O, S, CH₂, O--CH₂, S--CH₂ or CHOR¹ as Q, and CO, CR² R³ CO or CH═CHCO as L;

(2) O, S, CH₂, or CHOR¹ as Q, and CO or CR² R³ CO as L;

(3) O as Q, and CO or CR² R³ CO as L;

(4) O, S, CH₂, O--CH₂, or S--CH₂ as Q, and CO as L;

(5) O as Q, and CH═CHCO as L.

When the combination (1), (2) or (3) is chosen, R¹, R² and R³ represent independently hydrogen atom or C₁ -C₄ lower alkyl group, particularly hydrogen atom, methyl group or ethyl group.

In formula I!, Q in the naphthalene ring is substituted at 1- or 2-position of the naphthalene ring, and preferably at the 2-position.

In formula I! wherein the benzene ring has been substituted by Q, L and D, the relative position of Q and L may be ortho, meta or para, preferably para.

Naphthalene derivatives of this invention can be converted into pharmacologically acceptable solvates. The appropriate solvent includes water, methanol, ethanol, (n-, i-) propyl alcohol, (n-, t-) butanol, acetonitrile, acetone, methyl ethyl ketone, chloroform, ethyl acetate, diethyl ether, t-butyl methyl ether, benzene, toluene, DMF, DMSO, etc. Particularly, water, methanol, ethanol, (n-, i-)propyl alcohol and acetonitrile can be mentioned as preferred solvents.

In formula I!, when D represents CO₂ R⁴ wherein R⁴ represents hydrogen atom; when E represents CO₂ R⁵ wherein R⁵ is hydrogen atom; when G represents CO₂ R⁶ wherein R⁶ is a hydrogen atom; when E represents a tetrazol-5-yl group; or when G represents a tetrazol-5-yl group, the naphthalene derivative of this invention can be converted into pharmacologically acceptable, non-toxic cationic salts or their solvates if it is necessary. Such salts include salts combined with: alkali metal ions such as Na⁺, K⁺, etc.; alkali earth metal ions such as Mg²⁺, Ca²⁺, etc.; metal ions such as Al³⁺, Zn²⁺, etc.; organic base compounds ammonia, triethylamine, ethylenediamine, propanediamine, pyrrolidine, piperidine, piperazine, pyridine, lysine, choline, ethanolamine, N,N-dimethylethanolamine, 4-hydroxypiperidine, glucosamine, N-methylglucamine, etc. Among these, Na⁺, Ca²⁺, lysine, choline, N,N-dimethylethanolamine, N-methylglucamine are preferred. The appropriate solvent required for their solvates includes water, methanol, ethanol, (n-, i-)propyl alcohol, (n-, t-)butanol, acetonitrile, acetone, methyl ethyl ketone, chloroform, ethyl acetate, diethyl ether, t-butyl methyl ether, benzene, toluene, DMF, DMSO, etc. Among these, water, methanol, ethanol, (n-, i-)propyl alcohol and acetonitrile can be mentioned as preferred solvents.

In formula I!, when D represents NH₂, the naphthalene derivative of this invention can be converted into pharmacologically acceptable acid salts or their solvates if it is necessary. Such acids include mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, etc., or organic acids such as acetic acid, benzoic acid, fumaric acid, maleic acid, methanesulfonic acid, toluenesulfonic acid, etc. Among these, hydrochloric acid, sulfuric acid, acetic acid, fumaric acid, maleic acid, methanesulfonic acid, toluenesulfonic acid can be mentioned as preferred acids. Further, the solvents required for their solvates include water, methanol, (n-, i-) propyl alcohol, (n-, t-) buthanol, acetonitrile, acetone, methyl ethyl ketone, chloroform, ethyl acetate, diethyl ether, t-butyl methyl ether, benzene, toluene, DMF, DMSO, etc. Particularly, water, methanol, ethanol, (n-, i-)propyl alcohol, and acetonitrile can be mentioned as preferred solvents.

Preferred examples of naphthalene derivatives of this invention represented by formula I! are the compounds listed in Tables 1-1 to 1-18; their solvates of water, methanol, ethanol, (n-, i-) propyl alcohol, or acetonitrile; their salts of sodium, potassium, lysine, choline, N,N-dimethylethanol amine, N-methylglucamine, hydrochloric acid, sulfuric acid, acetic acid, fumaric acid, maleic acid, methanesulfonic acid, and toluenesulfonic acid; and the solvates of their salts of water, methanol, ethanol, (n-, i-)propyl alcohol, or acetonitrile. For a compound that has an asymmetric carbon atom(s) in its structure, all the optical isomers should be included in the compounds of this invention, and for a compound that has a carbon-carbon double bond(s) in its structure, all the geometrical isomers should be included. "tet" in Tables 1-1, 1-2, 1-15 and 1-16 represents tetrazol-5-yl group.

                                      TABLE 1-1                                    __________________________________________________________________________     (A = H, M = H)                                                                 1 #STR5##                                                                                                  Substituted Position                                                                     Substituted Position                     Compound No.                                                                           Q L  D         E    on Naphthalene*.sup.1)                                                                   on Benzene*.sup.2)                       __________________________________________________________________________     1101    0 CO H         CO.sub.2 Me                                                                         2-position                                                                               para                                     1102    0 CO H         CO.sub.2 Et                                                                         2-position                                                                               para                                     1103    0 CO H         CO.sub.2 tBu                                                                        2-position                                                                               para                                     1104    0 CO H         CO.sub.2 H                                                                          2-position                                                                               para                                     1105    0 CO H         H    2-position                                                                               para                                     1106    0 CO H         OH   2-position                                                                               para                                     1107    0 CO H         SO.sub.2 NH.sub.2                                                                   2-position                                                                               para                                     1108    0 CO H         CN   2-position                                                                               para                                     1109    0 CO H         tet  2-position                                                                               para                                     1110    0 CO H         CO.sub.2 Me                                                                         1-position                                                                               para                                     1111    0 CO H         CO.sub.2 H                                                                          1-position                                                                               para                                     1112    0 CO H         CO.sub.2 Me                                                                         2-position                                                                               meta                                     1113    0 CO H         CO.sub.2 H                                                                          2-position                                                                               meta                                     1114    0 CO NO.sub.2  CO.sub.2 Me                                                                         2-position                                                                               para                                     1115    0 CO NO.sub.2  CO.sub.2 Et                                                                         2-position                                                                               para                                     1116    0 CO NO.sub.2  CO.sub.2 H                                                                          2-position                                                                               para                                     1117    0 CO NH.sub.2  CO.sub.2 Me                                                                         2-position                                                                               para                                     1118    0 CO NH.sub.2  CO.sub.2 H                                                                          2-position                                                                               para                                     1119    0 CO CO.sub.2 Me                                                                              CO.sub.2 Me                                                                         2-position                                                                               para                                     1120    0 CO CO.sub.2 H                                                                               CO.sub.2 H                                                                          2-position                                                                               para                                     1121    0 CO  II!, G = CO.sub.2 Me                                                                    CO.sub.2 Me                                                                         2-position                                                                               para                                     1122    0 CO  II!, G = CO.sub.2 H                                                                     CO.sub.2 H                                                                          2-position                                                                               para                                     __________________________________________________________________________      *.sup.1) Position substituted by Q on naphthalene ring                         *.sup.2) Relative position of Q and L on the benzene ring that has been        substituted by Q, L and D                                                

                                      TABLE 1-2                                    __________________________________________________________________________     (A = H, M = H)                                                                 1 #STR6##                                                                                                      Substituted Position                                                                     Substituted Position                 Compound No.                                                                           Q L      D         E    on Naphthalene*.sup.1)                                                                   on Benzene*.sup.2)                   __________________________________________________________________________     1123    0 CH.sub.2 CO                                                                           H         CO.sub.2 Me                                                                         2-position                                                                               para                                 1124    0 CH.sub.2 CO                                                                           H         CO.sub.2 Et                                                                         2-position                                                                               para                                 1125    0 CH.sub.2 CO                                                                           H         CO.sub.2 tBu                                                                        2-position                                                                               para                                 1126    0 CH.sub.2 CO                                                                           H         CO.sub.2 H                                                                          2-position                                                                               para                                 1127    0 CH.sub.2 CO                                                                           H         H    2-position                                                                               para                                 1128    0 CH.sub.2 CO                                                                           H         OH   2-position                                                                               para                                 1129    0 CH.sub.2 CO                                                                           H         SO.sub.2 NH.sub.2                                                                   2-position                                                                               para                                 1130    0 CH.sub.2 CO                                                                           H         CN   2-position                                                                               para                                 1131    0 CH.sub.2 CO                                                                           H         tet  2-position                                                                               para                                 1132    0 CH.sub.2 CO                                                                           H         CO.sub.2 Me                                                                         1-position                                                                               para                                 1133    0 CH.sub.2 CO                                                                           H         CO.sub.2 H                                                                          1-position                                                                               para                                 1134    0 CH.sub.2 CO                                                                           H         CO.sub.2 Me                                                                         2-position                                                                               meta                                 1135    0 CH.sub.2 CO                                                                           H         CO.sub.2 H                                                                          2-position                                                                               meta                                 1136    0 CH.sub.2 CO                                                                           NO.sub.2  CO.sub.2 Me                                                                         2-position                                                                               para                                 1137    0 CH.sub.2 CO                                                                           NO.sub.2  CO.sub.2 Et                                                                         2-position                                                                               para                                 1138    0 CH.sub.2 CO                                                                           NO.sub.2  CO.sub.2 H                                                                          2-position                                                                               para                                 1139    0 CH.sub.2 CO                                                                           NH.sub.2  CO.sub.2 Me                                                                         2-position                                                                               para                                 1140    0 CH.sub.2 CO                                                                           NH.sub.2  CO.sub.2 H                                                                          2-position                                                                               para                                 1141    0 CH.sub.2 CO                                                                           CO.sub.2 Me                                                                              CO.sub.2 Me                                                                         2-position                                                                               para                                 1142    0 CH.sub.2 CO                                                                           CO.sub.2 H                                                                               CO.sub.2 H                                                                          2-position                                                                               para                                 1143    0 CH.sub.2 CO                                                                            II!, G = CO.sub.2 Me                                                                    CO.sub.2 Me                                                                         2-position                                                                               para                                 1144    0 CH.sub.2 CO                                                                            II!, G = CO.sub.2 H                                                                     CO.sub.2 H                                                                          2-position                                                                               para                                 1145    0 CH.sub.2 CH.sub.2 CO                                                                  H         CO.sub.2 Me                                                                         2-position                                                                               para                                 1146    0 CH.sub.2 CH.sub.2 CO                                                                  H         CO.sub.2 H                                                                          2-position                                                                               para                                 1147    0 CH═CHCO                                                                           H         CO.sub.2 Me                                                                         2-position                                                                               para                                 1148    0 CH═CHCO                                                                           H         CO.sub.2 H                                                                          2-position                                                                               para                                 __________________________________________________________________________      *.sup.1) Position substituted by Q on naphthalene ring                         *.sup.2) Relative position of Q and L on the benzene ring that has been        substituted by Q, L, and D                                               

                                      TABLE 1-3                                    __________________________________________________________________________     6 #STR7##                                                                                                                 Substituted Position                                                                     Substituted                                                                    Position                  Compound No                                                                            A                  Q L    D E    M on Naphthalene*.sup.1)                                                                   on                        __________________________________________________________________________                                                          Benzene*.sup.2)           1201    HO                 0 CO   H CO.sub.2 Me                                                                         H 2-position                                                                               para                      1202    HO                 0 CO   H CO.sub.2 H                                                                          H 2-position                                                                               para                      1203    MeO                0 CO   H CO.sub.2 Me                                                                         H 2-position                                                                               para                      1204    MeO                0 CO   H CO.sub.2 H                                                                          H 2-position                                                                               para                      1205                                                                                   2 #STR8##          0 CO   H CO.sub.2 Me                                                                         H 2-position                                                                               para                      1206                                                                                   2 #STR9##          0 CO   H CO.sub.2 H                                                                          H 2-position                                                                               para                      1207    HO                 0 CH.sub.2 CO                                                                         H CO.sub.2 Me                                                                         H 2-position                                                                               para                      1208    HO                 0 CH.sub.2 CO                                                                         H CO.sub.2 H                                                                          H 2-position                                                                               para                      1209                                                                                   3 #STR10##         0 CH.sub.2 CO                                                                         H CO.sub.2 Me                                                                         H 2-position                                                                               para                      1210                                                                                   3 #STR11##         0 CH.sub.2 CO                                                                         H CO.sub.2 H                                                                          H 2-position                                                                               para                      1211                                                                                   4 #STR12##         0 CH.sub.2 CO                                                                         H CO.sub.2 Me                                                                         H 2-position                                                                               para                      1212                                                                                   4 #STR13##         0 CH.sub.2 CO                                                                         H CO.sub.2 H                                                                          H 2-position                                                                               para                      1213                                                                                   5 #STR14##         0 CH.sub.2 CO                                                                         H CO.sub.2 Me                                                                         H 2-position                                                                               para                      1214                                                                                   5 #STR15##         0 CH.sub.2 CO                                                                         H CO.sub.2 H                                                                          H 2-position                                                                               para                      __________________________________________________________________________      *.sup.1) Position substituted by Q on naphthalene ring                         *.sup.2) Relative position of Q and L on the benzene ring that has been        substituted by Q, L and D                                                

                                      TABLE 1-4                                    __________________________________________________________________________     6 #STR16##                                                                                                                Subsitiuted Position                                                                     Substituted                                                                    Position                  Compound No                                                                            A                  Q L    D E    M on Naphthalene*.sup.1)                                                                   on                        __________________________________________________________________________                                                          Benzene*.sup.2)           1215                                                                                   7 #STR17##         0 CH.sub.2 CO                                                                         H CO.sub.2 Me                                                                         H 2-position                                                                               para                      1216                                                                                   7 #STR18##         0 CH.sub.2 CO                                                                         H CO.sub.2 H                                                                          H 2-position                                                                               para                      1217                                                                                   8 #STR19##         0 CH.sub.2 CO                                                                         H CO.sub.2 2 Me                                                                       H 2-position                                                                               para                      1218                                                                                   8 #STR20##         0 CH.sub.2 CO                                                                         H CO.sub.2 H                                                                          H 2-position                                                                               para                      1219                                                                                   9 #STR21##         0 CH.sub.2 CO                                                                         H CO.sub.2 Me                                                                         H 2-position                                                                               para                      1220                                                                                   9 #STR22##         0 CH.sub.2 CO                                                                         H CO.sub.2 H                                                                          H 2-position                                                                               para                      1221                                                                                   0 #STR23##         0 CH.sub.2 CO                                                                         H CO.sub.2 Me                                                                         H 2-position                                                                               para                      1222                                                                                   0 #STR24##         0 CH.sub.2 CO                                                                         H CO.sub.2 H                                                                          H 2-position                                                                               para                      1223                                                                                   2 #STR25##         0 CH.sub.2 CO                                                                         H CO.sub.2 Me                                                                         H 2-position                                                                               para                      1224                                                                                   2 #STR26##         0 CH.sub.2 CO                                                                         H CO.sub.2 H                                                                          H 2-position                                                                               para                      __________________________________________________________________________      *.sup.1) Position substituted by Q on naphthalene ring                         *.sup.2) Relative position of Q and L on the benzene ring that has been        substituted by Q, L and D                                                

                                      TABLE 1-5                                    __________________________________________________________________________     6 #STR27##                                                                                                                Substituted Position                                                                     Substituted                                                                    Position                  Compound No.                                                                           A              Q L      D E    M   on Naphthalene*.sup.1)                                                                   on                        __________________________________________________________________________                                                          Benzene*.sup.2)           1225                                                                                   1 #STR28##     0 CH.sub.2 CO                                                                           H CO.sub.2 Me                                                                         H   2-position                                                                               para                      1226                                                                                   1 #STR29##     0 CH.sub.2 CO                                                                           H CO.sub.2 H                                                                          H   2-position                                                                               para                      1227                                                                                   2 #STR30##     0 CH.sub.2 CO                                                                           H CO.sub.2 Me                                                                         H   2-position                                                                               para                      1228                                                                                   2 #STR31##     0 CH.sub.2 CO                                                                           H CO.sub.2 H                                                                          H   2-position                                                                               para                      1149    H              0 CH(Me)CO                                                                              H CO.sub.2 Me                                                                         H   2-position                                                                               para                      1150    H              0 CH(Me)CO                                                                              H CO.sub.2 H                                                                          H   2-position                                                                               para                      1151    H              0 CH(Me).sub.2 CO                                                                       H CO.sub.2 Me                                                                         H   2-position                                                                               para                      1152    H              0 CH(Me).sub.2 CO                                                                       H CO.sub.2 H                                                                          H   2-position                                                                               para                      1153    H              0 CO     H CO.sub.2 Me                                                                         3-Me                                                                               2-position                                                                               para                      1154    H              0 CO     H CO.sub.2 H                                                                          3-Me                                                                               2-position                                                                               para                      1155    H              0 CH.sub.2 CO                                                                           H CO.sub.2 Me                                                                         4-NO.sub.2                                                                         2-position                                                                               para                      1156    H              0 CH.sub.2 CO                                                                           H CO.sub.2 H                                                                          4-NO.sub.2                                                                         2-position                                                                               para                      1157    H              0 CH.sub.2 CO                                                                           H CO.sub.2 Me                                                                         4-F 2-position                                                                               para                      1158    H              0 CH.sub.2 CO                                                                           H CO.sub.2 H                                                                          4-F 2-position                                                                               para                      1159    H              0 CH.sub.2 CO                                                                           H CO.sub.2 Me                                                                         5-F 2-position                                                                               para                      1160    H              0 CH.sub.2 CO                                                                           H CO.sub.2 H                                                                          5-F 2-position                                                                               para                      1161    H              0 CH.sub.2 CO                                                                           H CO.sub.2 Me                                                                         5-Cl                                                                               2-position                                                                               para                      1162    H              0 CH.sub.2 CO                                                                           H CO.sub.2 H                                                                          5-Cl                                                                               2-position                                                                               para                      1163    H              0 CH.sub.2 CO                                                                           H CO.sub.2 Me                                                                         6-Me                                                                               2-position                                                                               para                      1164    H              0 CH.sub.2 CO                                                                           H CO.sub.2 H                                                                          6-Me                                                                               2-position                                                                               para                      __________________________________________________________________________      *.sup.1) Position substituted by Q on naphthalene ring                         *.sup.2) Relative position of Q and L on the benzene ring that has been        substituted by Q, L and D                                                

                                      TABLE 1-6                                    __________________________________________________________________________     6 #STR32##                                                                                                                Substituted Position                                                                     Substituted                                                                    Position                  Compound No.                                                                           A                  Q L    D E    M on Naphthalene*.sup.1)                                                                   on                        __________________________________________________________________________                                                          Benzene*.sup.2)           1229    MeO                0 CH.sub.2 CO                                                                         H CO.sub.2 Me                                                                         H 2-position                                                                               para                      1230    MeO                0 CH.sub.2 CO                                                                         H CO.sub.2 H                                                                          H 2-position                                                                               para                      1231                                                                                   3 #STR33##         0 CO   H CO.sub.2 Me                                                                         H 2-position                                                                               para                      1232                                                                                   3 #STR34##         0 CO   H CO.sub.2 H                                                                          H 2-position                                                                               para                      1233                                                                                   4 #STR35##         0 CO   H CO.sub.2 Me                                                                         H 2-position                                                                               para                      1234                                                                                   4 #STR36##         0 CO   H CO.sub.2 H                                                                          H 2-position                                                                               para                      1235                                                                                   5 #STR37##         0 CO   H CO.sub.2 Me                                                                         H 2-position                                                                               para                      1236                                                                                   5 #STR38##         0 CO   H CO.sub.2 H                                                                          H 2-position                                                                               para                      __________________________________________________________________________      *.sup.1) Position substituted by Q on naphthalene ring                         *.sup.2) Relative position of Q and L on the benzene ring that has been        substituted by Q, L and D                                                

                                      TABLE 1-7                                    __________________________________________________________________________     6 #STR39##                                                                                                               Substituted Position                                                                     Substituted Position       Compound No.                                                                           A                   Q L D E     M on Naphthalene*.sup.1)                                                                   on Benzene*.sup.2)         __________________________________________________________________________     1237                                                                                   7 #STR40##          0 CO                                                                               H CO.sub.2 Me                                                                          H 2-position                                                                               para                       1238                                                                                   7 #STR41##          0 CO                                                                               H CO.sub.2 H                                                                           H 2-position                                                                               para                       1239                                                                                   8 #STR42##          0 CO                                                                               H CO.sub.2 Me                                                                          H 2-position                                                                               para                       1240                                                                                   8 #STR43##          0 CO                                                                               H CO.sub.2 H                                                                           H 2-position                                                                               para                       1241                                                                                   9 #STR44##          0 CO                                                                               H CO.sub.2 Me                                                                          H 2-position                                                                               para                       1242                                                                                   9 #STR45##          0 CO                                                                               H CO.sub.2 H                                                                           H 2-position                                                                               para                       1243                                                                                   0 #STR46##          0 CO                                                                               H CO.sub.2 Me                                                                          H 2-position                                                                               para                       1244                                                                                   0 #STR47##          0 CO                                                                               H CO.sub.2 H                                                                           H 2-position                                                                               para                       __________________________________________________________________________      *.sup.1) Position substituted by Q on naphthalene ring                         *.sup.2) Relative position of Q and L on the benzene ring that has been        substituted by Q, L and D                                                

                                      TABLE 1-8                                    __________________________________________________________________________     6 #STR48##                                                                                                         Substituted Position                                                                     Substituted Position             Compound No.                                                                           A              Q L D E    M on Naphthalene*.sup.1)                                                                   on Benzene*.sup.2)               __________________________________________________________________________     1247                                                                                   1 #STR49##     0 CO                                                                               H CO.sub.2 Me                                                                         H 2-Position                                                                               para                             1248                                                                                   1 #STR50##     0 CO                                                                               H CO.sub.2 H                                                                          H 2-Position                                                                               para                             1249                                                                                   2 #STR51##     0 CO                                                                               H CO.sub.2 Me                                                                         H 2-Position                                                                               para                             1250                                                                                   2 #STR52##     0 CO                                                                               H CO.sub.2 H                                                                          H 2-Position                                                                               para                             __________________________________________________________________________      *.sup.1) Position substituted by Q on naphthalene ring                         *.sup.2) Relative position of Q and L on the benzene ring that has been        substituted by Q, L and D                                                

                                      TABLE 1-9                                    __________________________________________________________________________     6 #STR53##                                                                     Compound                                   Substituted Position                                                                     Substituted                                                                    Position                  No.   A                   Q L    D  E    M on Naphthalene*.sup.1)                                                                   on                        __________________________________________________________________________                                                          Benzene*.sup.2)           1251  HO                  0 CO   NO.sub.2                                                                          CO.sub.2 Me                                                                         H 2-Position                                                                               para                      1252  HO                  0 CO   NO.sub.2                                                                          CO.sub.2 H                                                                          H 2-Position                                                                               para                      1253  MeO                 0 CO   NO.sub.2                                                                          CO.sub.2 Me                                                                         H 2-Position                                                                               para                      1254  MeO                 0 CO   NO.sub.2                                                                          CO.sub.2 H                                                                          H 2-Position                                                                               para                      1255                                                                                 2 #STR54##          0 CO   NO.sub.2                                                                          CO.sub.2 Me                                                                         H 2-Position                                                                               para                      1256                                                                                 2 #STR55##          0 CO   NO.sub.2                                                                          CO.sub.2 H                                                                          H 2-Position                                                                               para                      1257  HO                  0 CH.sub.2 CO                                                                         NO.sub.2                                                                          CO.sub.2 Me                                                                         H 2-Position                                                                               para                      1258  HO                  0 CH.sub.2 CO                                                                         NO.sub.2                                                                          CO.sub.2 H                                                                          H 2-Position                                                                               para                      1259                                                                                 3 #STR56##          0 CH.sub.2 CO                                                                         NO.sub.2                                                                          CO.sub.2 Me                                                                         H 2-Position                                                                               para                      1260                                                                                 3 #STR57##          0 CH.sub.2 CO                                                                         NO.sub.2                                                                          CO.sub.2 H                                                                          H 2-Position                                                                               para                      1261                                                                                 4 #STR58##          0 CH.sub.2 CO                                                                         NO.sub.2                                                                          CO.sub.2 Me                                                                         H 2-Position                                                                               para                      1262                                                                                 4 #STR59##          0 CH.sub.2 CO                                                                         NO.sub.2                                                                          CO.sub.2 H                                                                          H 2-Position                                                                               para                      1264                                                                                 5 #STR60##          0 CH.sub.2 CO                                                                         NO.sub.2                                                                          CO.sub.2 Me                                                                         H 2-Position                                                                               para                      1264                                                                                 5 #STR61##          0 CH.sub.2 CO                                                                         NO.sub.2                                                                          CO.sub.2 H                                                                          H 2-Position                                                                               para                      __________________________________________________________________________      *.sup.1) Position substituted by Q on naphthalene ring                         *.sup.2) Relative position of Q and L on the benzene ring that has been        substituted by Q, L and D                                                

                                      TABLE 1-10                                   __________________________________________________________________________     1 #STR62##                                                                     Compound                                  Substituted Position                                                                     Substituted Position       No.   A                  Q L    D  E    M on Naphthalene*.sup.1)                                                                   on Benzene*.sup.2)         __________________________________________________________________________     1265                                                                                 2 #STR63##         0 CH.sub.2 CO                                                                         NO.sub.2                                                                          CO.sub.2 Me                                                                         H 2-Position                                                                               para                       1266                                                                                 2 #STR64##         0 CH.sub.2 CO                                                                         NO.sub.2                                                                          CO.sub.2 H                                                                          H 2-Position                                                                               para                       1267                                                                                 3 #STR65##         0 CH.sub.2 CO                                                                         NO.sub.2                                                                          CO.sub.2 Me                                                                         H 2-Position                                                                               para                       1268                                                                                 3 #STR66##         0 CH.sub.2 CO                                                                         NO.sub.2                                                                          CO.sub.2 H                                                                          H 2-Position                                                                               para                       1269                                                                                 4 #STR67##         0 CH.sub.2 CO                                                                         NO.sub.2                                                                          CO.sub.2 Me                                                                         H 2-Position                                                                               para                       1270                                                                                 4 #STR68##         0 CH.sub.2 CO                                                                         NO.sub.2                                                                          CO.sub.2 H                                                                          H 2-Position                                                                               para                       1271                                                                                 5 #STR69##         0 CH.sub.2 CO                                                                         NO.sub.2                                                                          CO.sub.2 Me                                                                         H 2-Position                                                                               para                       1272                                                                                 5 #STR70##         0 CH.sub.2 CO                                                                         NO.sub.2                                                                          CO.sub.2 H                                                                          H 2-Position                                                                               para                       1273                                                                                 6 #STR71##         0 CH.sub.2 CO                                                                         NO.sub.2                                                                          CO.sub.2 Me                                                                         H 2-Position                                                                               para                       1274                                                                                 6 #STR72##         0 CH.sub.2 CO                                                                         NO.sub.2                                                                          CO.sub.2 H                                                                          H 2-Position                                                                               para                       __________________________________________________________________________      *.sup.1) Position substituted by Q on naphthalene ring                         *.sup.2) Relative position of Q and L on the benzene ring that has been        substituted by Q, L and D                                                

                                      TABLE 1-11                                   __________________________________________________________________________     1 #STR73##                                                                                                                Substituted Position                                                                     Substituted                                                                    Position                  Compound No.                                                                           A               Q  L    D  E    M  on Naphthalene*.sup.1)                                                                   on                        __________________________________________________________________________                                                          Benzene*.sup.2)           1275                                                                                   7 #STR74##      0  CH.sub.2 CO                                                                         NO.sub.2                                                                          CO.sub.2 Me                                                                         H  2-Position                                                                               para                      1276                                                                                   7 #STR75##      0  CH.sub.2 CO                                                                         NO.sub.2                                                                          CO.sub.2 H                                                                          H  2-Position                                                                               para                      1277                                                                                   8 #STR76##      0  CH.sub.2 CO                                                                         NO.sub.2                                                                          CO.sub.2 Me                                                                         H  2-Position                                                                               para                      1278                                                                                   8 #STR77##      0  CH.sub.2 CO                                                                         NO.sub.2                                                                          CO.sub.2 H                                                                          H  2-Position                                                                               para                      __________________________________________________________________________      *.sup.1) Position substituted by Q on naphthalene ring                         *.sup.2) Relative position of Q and L on the benzene ring that has been        substituted by Q, L and D                                                

                                      TABLE 1-12                                   __________________________________________________________________________     1 #STR78##                                                                     Compound                                  Substituted Position                                                                     Substituted Position       No.   A                  Q L    D  E    M on Naphthalene*.sup.1)                                                                   on Benzene*.sup.2)         __________________________________________________________________________     1279  MeO                0 CH.sub.2 CO                                                                         NO.sub.2                                                                          CO.sub.2 Me                                                                         H 2-Position                                                                               para                       1280  MeO                0 CH.sub.2 CO                                                                         NO.sub.2                                                                          CO.sub.2 H                                                                          H 2-Position                                                                               para                       1281                                                                                 9 #STR79##         0 CO   NO.sub.2                                                                          CO.sub.2 Me                                                                         H 2-Position                                                                               para                       1282                                                                                 9 #STR80##         0 CO   NO.sub.2                                                                          CO.sub.2 H                                                                          H 2-Position                                                                               para                       1283                                                                                 0 #STR81##         0 CO   NO.sub.2                                                                          CO.sub.2 Me                                                                         H 2-Position                                                                               para                       1284                                                                                 0 #STR82##         0 CO   NO.sub.2                                                                          CO.sub.2 H                                                                          H 2-Position                                                                               para                       1285                                                                                 1 #STR83##         0 CO   NO.sub.2                                                                          CO.sub.2 Me                                                                         H 2-Position                                                                               para                       1286                                                                                 1 #STR84##         0 CO   NO.sub.2                                                                          CO.sub.2 H                                                                          H 2-Position                                                                               para                       __________________________________________________________________________      *.sup.1) Position substituted by Q on naphthalene ring                         *.sup.2) Relative position of Q and L on the benzene ring that has been        substituted by Q, L and D                                                

                                      TABLE 1-13                                   __________________________________________________________________________     1 #STR85##                                                                                                                Substituted Position                                                                     Subsitiuted                                                                    Position                  Compound No.                                                                           A                   Q L  D  E    M on Naphthalene*.sup.1)                                                                   on                        __________________________________________________________________________                                                          Benzene*.sup.2)           1287                                                                                   2 #STR86##          0 CO NO.sub.2                                                                          CO.sub.2 Me                                                                         H 2-Position                                                                               para                      1288                                                                                   2 #STR87##          0 CO NO.sub.2                                                                          CO.sub.2 H                                                                          H 2-Position                                                                               para                      1289                                                                                   3 #STR88##          0 CO NO.sub.2                                                                          CO.sub.2 Me                                                                         H 2-Position                                                                               para                      1290                                                                                   3 #STR89##          0 CO NO.sub.2                                                                          CO.sub.2 H                                                                          H 2-Position                                                                               para                      1291                                                                                   4 #STR90##          0 CO NO.sub.2                                                                          CO.sub.2 Me                                                                         H 2-Position                                                                               para                      1292                                                                                   4 #STR91##          0 CO NO.sub.2                                                                          CO.sub.2 H                                                                          H 2-Position                                                                               para                      1293                                                                                   5 #STR92##          0 CO NO.sub.2                                                                          CO.sub.2 Me                                                                         H 2-Position                                                                               para                      1294                                                                                   5 #STR93##          0 CO NO.sub.2                                                                          CO.sub.2 H                                                                          H 2-Position                                                                               para                      __________________________________________________________________________      *.sup.1) Position substituted by Q on naphthalene ring                         *.sup.2) Relative position of Q and L on the benzene ring that has been        substituted by Q, L and D                                                

                                      TABLE 1-14                                   __________________________________________________________________________     1 #STR94##                                                                                                           Substituted Position                                                                     Substituted Position           Compound No.                                                                           A              Q L  D  E    M on Naphthalene*.sup.1)                                                                   on Benzene*.sup.2)             __________________________________________________________________________     1297                                                                                   7 #STR95##     0 CO NO.sub.2                                                                          CO.sub.2 Me                                                                         H 2-position                                                                               para                           1298                                                                                   7 #STR96##     0 CO NO.sub.2                                                                          CO.sub.2 H                                                                          H 2-position                                                                               para                           1299                                                                                   8 #STR97##     0 CO NO.sub.2                                                                          CO.sub.2 Me                                                                         H 2-position                                                                               para                           1300                                                                                   8 #STR98##     0 CO NO.sub.2                                                                          CO.sub.2 H                                                                          H 2-position                                                                               para                           __________________________________________________________________________      *.sup.1) Position substituted by Q on naphthalene ring                         *.sup.2) Relative position of Q and L on the benzene ring that has been        substituted by Q, L and D                                                

                                      TABLE 1-15                                   __________________________________________________________________________     (A = H, M = H)                                                                 3 #STR99##                                                                                              Substituted Position                                                                     Substituted Position                        Compound No.                                                                           Q L      D  E    on Naphthalene*.sup.1)                                                                   on Benzene*.sup.2)                          __________________________________________________________________________     3101    S CO     H  CO.sub.2 Me                                                                         2-position                                                                               para                                        3102    S CO     H  CO.sub.2 H                                                                          2-position                                                                               para                                        3103    S CO     H  CN   2-position                                                                               para                                        3104    S CO     H  tet  2-position                                                                               para                                        3105    S CO     NO.sub.2                                                                          CO.sub.2 Me                                                                         2-position                                                                               para                                        3106    S CO     NO.sub.2                                                                          CO.sub.2 H                                                                          2-position                                                                               para                                        3107    S CH.sub.2 CO                                                                           H  CO.sub.2 Me                                                                         2-position                                                                               para                                        3108    S CH.sub.2 CO                                                                           H  CO.sub.2 H                                                                          2-position                                                                               para                                        3109    S CH.sub.2 CO                                                                           H  CN   2-position                                                                               para                                        3110    S CH.sub.2 CO                                                                           H  tet  2-position                                                                               para                                        3111    S CH.sub.2 CO                                                                           NO.sub.2                                                                          CO.sub.2 Me                                                                         2-position                                                                               para                                        3112    S CH.sub.2 CO                                                                           NO.sub.2                                                                          CO.sub.2 H                                                                          2-position                                                                               para                                        3113    S CH.sub.2 CH.sub.2 CO                                                                  H  CO.sub.2 Me                                                                         2-position                                                                               para                                        3114    S CH.sub.2 CH.sub.2 CO                                                                  H  CO.sub.2 H                                                                          2-position                                                                               para                                        3115    S CH═CHCO                                                                           H  CO.sub.2 Me                                                                         2-position                                                                               para                                        3116    S CH═CHCO                                                                           H  CO.sub.2 H                                                                          2-position                                                                               para                                        __________________________________________________________________________      *.sup.1) Position substituted by Q on naphthalene ring                         *.sup.2) Relative position of Q and L on the benzene ring that has been        substituted by Q, L and D                                                

                                      TABLE 1-16                                   __________________________________________________________________________     (A = H, M = H)                                                                 3 #STR100##                                                                                              Substituted Position                                                                     Substituted Position                       Compound No.                                                                           Q  L      D  E    on Naphthalene*.sup.1)                                                                   on Benzene*.sup.2)                         __________________________________________________________________________     4101    CH.sub.2                                                                          CO     H  CO.sub.2 Me                                                                         2-position                                                                               para                                       4102    CH.sub.2                                                                          CO     H  CO.sub.2 Et                                                                         2-position                                                                               para                                       4103    CH.sub.2                                                                          CO     H  CO.sub.2 H                                                                          2-position                                                                               para                                       4104    CH.sub.2                                                                          CO     H  H    2-position                                                                               para                                       4105    CH.sub.2                                                                          CO     H  OH   2-position                                                                               para                                       4106    CH.sub.2                                                                          CO     H  SO.sub.2 NH.sub.2                                                                   2-position                                                                               para                                       4107    CH.sub.2                                                                          CO     H  tet  2-position                                                                               para                                       4108    CH.sub.2                                                                          CO     H  CO.sub.2 Me                                                                         1-position                                                                               para                                       4109    CH.sub.2                                                                          CO     H  CO.sub.2 H                                                                          1-position                                                                               para                                       4110    CH.sub.2                                                                          CO     NO.sub.2                                                                          CO.sub.2 Me                                                                         2-position                                                                               para                                       4111    CH.sub.2                                                                          CO     NO.sub.2                                                                          CO.sub.2 H                                                                          2-position                                                                               para                                       4112    CH.sub.2                                                                          CH.sub.2 CO                                                                           H  CO.sub.2 Me                                                                         2-position                                                                               para                                       4113    CH.sub.2                                                                          CH.sub.2 CO                                                                           H  CO.sub.2 Et                                                                         2-position                                                                               para                                       4114    CH.sub.2                                                                          CH.sub.2 CO                                                                           H  CO.sub.2 H                                                                          2-position                                                                               para                                       4115    CH.sub.2                                                                          CH.sub.2 CO                                                                           H  H    2-position                                                                               para                                       4116    CH.sub.2                                                                          CH.sub.2 CO                                                                           H  OH   2-position                                                                               para                                       4117    CH.sub.2                                                                          CH.sub.2 CO                                                                           H  SO.sub.2 NH.sub.2                                                                   2-position                                                                               para                                       4118    CH.sub.2                                                                          CH.sub.2 CO                                                                           H  tet  2-position                                                                               para                                       4119    CH.sub.2                                                                          CH.sub.2 CO                                                                           H  CO.sub.2 Me                                                                         1-position                                                                               para                                       4120    CH.sub.2                                                                          CH.sub.2 CO                                                                           H  CO.sub.2 H                                                                          1-position                                                                               para                                       4121    CH.sub.2                                                                          CH.sub.2 CO                                                                           NO.sub.2                                                                          CO.sub.2 Me                                                                         2-position                                                                               para                                       4122    CH.sub.2                                                                          CH.sub.2 CO                                                                           NO.sub.2                                                                          CO.sub.2 H                                                                          2-position                                                                               para                                       4123    CH.sub.2                                                                          CH.sub.2 CH.sub.2 CO                                                                  H  CO.sub.2 Me                                                                         2-positlon                                                                               para                                       4124    CH.sub.2                                                                          CH.sub.2 CH.sub.2 CO                                                                  H  CO.sub.2 H                                                                          2-position                                                                               para                                       4125    CH.sub.2                                                                          CH═CHCO                                                                           H  CO.sub.2 Me                                                                         2-position                                                                               para                                       4126    CH.sub.2                                                                          CH═CHCO                                                                           H  CO.sub.2 H                                                                          2-position                                                                               para                                       __________________________________________________________________________      *.sup.1) Position substituted by Q on naphthalene ring                         *.sup.2) Relative position of Q and L on the benzene ring that has been        substituted by Q, L and D                                                

                                      TABLE 1-17                                   __________________________________________________________________________     (A = H, M = H)                                                                 3 #STR101##                                                                                               Substituted Position                                                                     Substituted Position                      Compound No.                                                                           Q     L    D  E    on Naphthalene*.sup.1)                                                                   on Benzene*.sup.2)                        __________________________________________________________________________     5101    OCH.sub.2                                                                            CO   H  CO.sub.2 Me                                                                         2-position                                                                               para                                      5102    OCH.sub.2                                                                            CO   H  CO.sub.2 H                                                                          2-position                                                                               para                                      5103    OCH.sub.2                                                                            CH.sub.2 CO                                                                         H  CO.sub.2 Me                                                                         2-position                                                                               para                                      5104    OCH.sub.2                                                                            CH.sub.2 CO                                                                         H  CO.sub.2 H                                                                          2-position                                                                               para                                      6101    SCH.sub.2                                                                            CO   H  CO.sub.2 Me                                                                         2-position                                                                               para                                      6102    SCH.sub.2                                                                            CO   H  CO.sub.2 H                                                                          2-position                                                                               para                                      6103    SCH.sub.2                                                                            CH.sub.2 CO                                                                         H  CO.sub.2 Me                                                                         2-position                                                                               para                                      6104    SCH.sub.2                                                                            CH.sub.2 CO                                                                         H  CO.sub.2 H                                                                          2-position                                                                               para                                      7101    CO    CO   H  CO.sub.2 Me                                                                         2-position                                                                               para                                      7102    CO    CO   H  CO.sub.2 H                                                                          2-position                                                                               para                                      7103    CO    CO   H  CO.sub.2 Me                                                                         1-position                                                                               para                                      7104    CO    CO   H  CO.sub.2 H                                                                          1-position                                                                               para                                      7105    CO    CH.sub.2 CO                                                                         H  CO.sub.2 Me                                                                         2-position                                                                               para                                      7106    CO    CH.sub.2 CO                                                                         H  CO.sub.2 H                                                                          2-position                                                                               para                                      8101    CH(OMe)                                                                              CO   H  CO.sub.2 Me                                                                         2-position                                                                               para                                      8102    CH(OMe)                                                                              CO   H  CO.sub.2 H                                                                          2-position                                                                               para                                      8103    CH(OMe)                                                                              CO   NO.sub.2                                                                          CO.sub.2 Me                                                                         2-position                                                                               para                                      8104    CH(OMe)                                                                              CO   NO.sub.2                                                                          CO.sub.2 H                                                                          2-position                                                                               para                                      8105    CH(OMe)                                                                              CH.sub.2 CO                                                                         H  CO.sub.2 Me                                                                         2-position                                                                               para                                      8106    CH(OMe)                                                                              CH.sub.2 CO                                                                         H  CO.sub.2 H                                                                          2-position                                                                               para                                      8107    CH(OMe)                                                                              CH.sub.2 CO                                                                         NO.sub.2                                                                          CO.sub.2 Me                                                                         2-position                                                                               para                                      8108    CH(OMe)                                                                              CH.sub.2 CO                                                                         NO.sub.2                                                                          CO.sub.2 H                                                                          2-position                                                                               para                                      __________________________________________________________________________      *.sup.1) Position substituted by Q naphthalene ring                            *.sup.2) Relative position of Q and L on the benzene ring that has been        substituted by Q, L and D                                                

                                      TABLE 1-18                                   __________________________________________________________________________     (A = H, M = H)                                                                 3 #STR102##                                                                                              Substituted Position                                                                     Substituted Position                       Compound No.                                                                           Q    L    D  E    on Naphthalene*.sup.1)                                                                   on Benzene*.sup.2)                         __________________________________________________________________________     8109    CH(OEt)                                                                             CO   H  CO.sub.2 Me                                                                         2-position                                                                               para                                       8110    CH(OEt)                                                                             CO   H  CO.sub.2 H                                                                          2-position                                                                               para                                       8111    CH(OEt)                                                                             CO   NO.sub.2                                                                          CO.sub.2 Me                                                                         2-position                                                                               para                                       8112    CH(OEt)                                                                             CO   NO.sub.2                                                                          CO.sub.2 H                                                                          2-position                                                                               para                                       8113    CH(OEt)                                                                             CH.sub.2 CO                                                                         H  CO.sub.2 Me                                                                         2-position                                                                               para                                       8114    CH(OEt)                                                                             CH.sub.2 CO                                                                         H  CO.sub.2 H                                                                          2-position                                                                               para                                       8115    CH(OEt)                                                                             CH.sub.2 CO                                                                         NO.sub.2                                                                          CO.sub.2 Me                                                                         2-position                                                                               para                                       8116    CH(OEt)                                                                             CH.sub.2 CO                                                                         NO.sub.2                                                                          CO.sub.2 H                                                                          2-position                                                                               para                                       __________________________________________________________________________      *.sup.1) Position substituted by Q on naphthalene ring                         *.sup.2) Relative position of Q and L on the benzene ring that has been        substituted by Q, L and D                                                

The naphthalene derivatives of this invention represented by formula I!, their pharmacologically acceptable salts, or their pharmacologically acceptable solvates can be prepared, for example, by the following scheme except the compounds in which A is a hydroxy group or D is an amino group. Namely, a carboxylic acid III! having a naphthalene moiety is condensed with an aniline derivative IV!, to afford target compound I!. ##STR103##

What A, Q, L, D, E and M stands for in above formulas is as defined above.

The starting material III! can be obtained by a method publicly known.

The condensation can be performed by two methods: one with the use of an acyl halide, and the other without the use of an acyl halide. These two methods are basically known.

For the compound I! prepared by way of an acyl halide, the compound III! is allowed to react with a halogenating agent such as oxalyl chloride or thionyl chloride under the presence or absence of an additive such as DMF or the like, to give an acyl halide of III! which is then allowed to react with the compound IV! under the presence or absence of a base, to give the compound I!.

On the other hand, with the method in which an acyl halide is not utilized, the compound III! is activated by the use of one of various activators such as anhydrous mixed acids, carbodiimides, imidazoles, haloester phosphates, cyanoester phosphates, etc., and the resulting compound is allowed to react with the compound IV! to give the compound I!.

Further, when the naphthalene derivative of this invention represented by formula I!, its pharmacologically acceptable salt, or its pharmacologically acceptable solvate has a hydroxy group as A, it can be prepared, for example, by the following scheme. Namely, a carboxylic acid V! having a naphthalene moiety which has been substituted by A' whose hydroxy group has been protected by an appropriate protecting group is condensed with an aniline derivative VI! to produce a compound VII!. The compound VII! is then deprotected to give the compound I!(A=OH). ##STR104##

The definitions of A, Q, L, D, E and M in above formulas are as described above. A' represents a hydrogen group protected by an appropriate protecting group.

The protecting group and its removal method may occur in following combinations to take representative examples: A' having its hydroxy group protected by a methoxy group and deprotected by Me₃ SiI, EtSNa or BBr₃ ; A' having its hydroxy group protected by an allyloxy group and deprotected by Paradium catalyst; and A' having its hydroxy group protected by a benzyloxy group and deprotected by hydrogenation.

The starting material V! can be obtained by a publicly known method.

The condensation of the compounds V! and VI! can be performed in the same manner as in the condensation of the compounds III! and IV! described above.

Further, when the naphthalene derivative of this invention represented by formula I!, its pharmacologically acceptable salt, or its pharmacologically acceptable solvate has an amino group as D, it can be prepared, for example, by the following scheme. Namely, carboxylic acid VIII!, having a naphthalene moiety and a protected amino substituent or a substituent convertible into amino group as D', is condensed with aniline derivative IX! to give compound X!. Compound X! is deprotected or converted to an amino group, to give the compound I! (D=NH₂). ##STR105##

The definitions of A, Q, L, D, E and M in above formulas are as described above. D' represents an amino group protected by an appropriate protecting group, or a functional group convertible to an amino group.

Representative examples of the protecting group and its removal method are listed in following combinations: D' having its amino group protected by a benzyl carbamoyl group and deprotected by hydrogenation; D' having its amino group protected by 9-fluorenylmethyl carbamoyl group and deprotected by an organic base such as piperidine; and D' having its amino group protected by t-butyl carbamoyl group and deprotected by an acid or the like. Further, the functional group convertible to an amino group includes, for example, D'=nitro group. A nitro group can be converted through a reduction reaction to an amino group.

The starting material VIII! can be obtained by a publicly known method.

The condensation of the compounds VIII! and IX! can be performed as in the compounds III! and IV! described above.

If need be, the compound I! thus obtained, when D represents CO₂ R⁴ wherein R⁴ is a C₁ -C₄ lower alkyl group; when E represents CO₂ R⁵ wherein R⁵ is a C₁ -C₄ lower alkyl group; or when G represents CO₂ R⁶ wherein R⁶ is a C₁ -C₄ lower alkyl group, can be hydrolyzed under an acidic or alkaline condition, to afford a compound wherein R⁴, R⁵ or R⁶ represents a hydrogen atom.

Further, the compound I! thus obtained, when E represents CN or G represents CN, is allowed to react with an azide compound to give a compound wherein E or G represents tetrazol-5-yl if it is necessary. In addition, the compound I! thus obtained can be converted to a pharmacologically acceptable solvate as described above if it is necessary.

Furthermore, the compound I! thus obtained (wherein D represents CO₂ R⁴ wherein R⁴ is a hydrogen atom; E represents CO₂ R⁵ wherein R⁵ is a hydrogen atom; G represents CO₂ R⁶ wherein R⁶ is a hydrogen atom; E represents a tetrazol-5-yl group; G represents a tetrazol-5-yl group; or D represents NH₂) can be converted to a pharmacologically acceptable salt or its solvate as described above if need be.

According to above procedures, the naphthalene derivatives of this invention represented by above formula I!, their pharmacologically acceptable salts, and their pharmacologically acceptable solvates can be obtained.

The naphthalene derivatives of this invention, their pharmacologically acceptable salts or their pharmacologically acceptable solvates can be administered orally or via parenteral routes such as venous, subcutaneous, muscular, percutaneous, rectal, intranasal, ophthalmic routes, or through inhalation.

The pharmaceutical dosage formulation appropriate for oral administration includes, for example, tablets, pills, granules, powders, liquids, suspensions, syrups, capsules, etc.

Tablets can be formulated by conventional methods with an excipient(s) such as lactose, starch, crystalline cellulose or the like, a binder(s) such as carboxymethyl cellulose, methyl cellulose, polyvinyl pyrrolidone or the like, and a disintegrator(s) such as sodium alginate, sodium hydrogencarbonate, sodium laurylsulfate or the like.

Pills, granules and powders can be formulated by conventional methods with such excipient(s) and others as described above.

Liquids, suspensions and syrups can be formulated by conventional methods with glycerin esters such as tricaprylin, triacetin or the like; alcohols such as ethanol or the like; water; or vegetable oils such as corn oil, cotton seed oil, coconut oil, almond oil, peanut oil, olive oil or the like.

The compound in the form of granules, powder or liquid may be introduced into the capsules made of, say, gelatin.

For venous, subcutaneous or intramuscular injection, a sterile aqueous or nonaqueous solutions can be prepared. In order to prepare aqueous solutions from the compound, for example, physiological saline is used. In order to prepare nonaqueous solutions from the compound, used are propylene glycol, polyethylene glycol, a vegetable oil such as olive oil, or an injectable organic ester such as ethyl oleate or the like. To the preparation thus produced should be added a tonicity balancer(s), a disinfectant(s), a penetrant(s), an emulsifier(s), a dispersant(s), a stabilizer(s) and the like. The preparation can be sterilized by filtration through a filter impermeable to bacteria, by treatment with a disinfectant, or by heat or irradiation in a proper manner. In addition, a sterilized solid preparation may be produced, and just prior to use it can be dissolved in sterilized water or sterilized injection solution.

The dosage form appropriate for percutaneous application includes, for example, ointment and cream. According to the conventional methods, ointment can be formulated with oils such as castor oil, olive oil or the like, or vaseline. Cream can be formulated with fats; diethylene glycol; and an emulsifier such as sorbitan monofatty-acid ester.

The dosage form appropriate for rectal application includes typically suppositories based on the use of gelatin soft capsules.

The preparation appropriate for intranasal application includes liquid or powdery composition. The base of a liquid preparation includes water, salt water, phosphate buffer or acetate buffer. In addition, the preparation can contain a surfactant(s), an antioxidant(s), a stabilizer(s), a preserver(s), and a viscosity adjuster(s). The appropriate base for the powdery preparation should have a water-absorbing property, and includes, for example, water soluble polyacrylates such as sodium polyacrylate, potassium polyacrylate, ammonium polyacrylate or the like; cellulose lower alkylethers such as methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxylmethyl cellulose sodium or the like; polyethyleneglycol polyvinylpyrrolidone; amylose; and pluran; and further, water insoluble celluloses such as crystalline cellulose,-cellulose, cross-linked carboxylmethyl cellulose sodium or the like; starches such as hydroxypropyl starch, carboxymethyl starch, cross-linked starch, amylose, amylopectin, pectin or the like; proteins such as gelatin, casein, casein sodium or the like; gums such as arabic gum, tragacanth gum, glucomannan or the like; and cross-linked vinyl polymers such as polyvinyl polypyrrolidone, cross-linked polyacrylate and its salts, cross-linked polyvinyl alcohol, polyhydroxyethyl methacrylate or the like, and they can be used in combinations. To the powdery preparation can be added an antioxidant (s), a pigment(s), a preservative(s), a disinfectant(s), an antiseptic (s) or the like. The liquid or powdery preparation can be administered through a sprayer.

The dosage form appropriate for ophthalmic drop lotion is aqueous or nonaqueous solutions of the compound. For the compound to be converted to an aqueous solutions for ophthalmic use, the solvent to be used includes sterilized, purified water, physiological saline, or appropriate aqueous solvents. Thus, when it is dissolved in sterilized, purified water, it gives an aqueous solutions for ophthalmic use; when a viscosity adjuster such as carboxymethyl cellulose, methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone or the like is added, it gives a viscous solution for ophthalmic use; when a suspending agent such as a surfactant or a viscosity adjusting polymer is added, it gives an aqueous suspension for ophthalmic use; and when a solubilizer such as a non-ionic surfactant is added, it gives a solubilized solution for ophthalmic use. The solvent to be used for preparation of nonaqueous solutions of the compound for ophthalmic use includes nonaqueous solvents for injection. When a vegetable oil, liquid paraffin, mineral oil, propylene glycol or the like is used, the resulting fluid gives a nonaqueous solutions for ophthalmic use; when a thixotropic glue such as aluminum monostearate or the like is added, the resulting fluid gives a nonaqueous suspension for ophthalmic use. To the preparation thus produced can be added as appropriate a tonicity balancer(s), a preservative(s), a buffer(s), an emulsifier(s), a stabilizer(s) and the like. The preparation can be sterilized by filteration through a filter impermeable to bacteria, by treatment with a disinfectant, or by heat or irradiation in a proper manner. Further, a sterilized solid preparation may be produced, and just prior to use it can be dissolved or suspended in a sterilized solution.

The dosage form appropriate for ophthalmic use except eye-drop lotion includes the following. Formulation with vaseline may give an ointment for ophthalmic use; formulation with a solution such as diluted iodine tincture, zinc sulfate, methylrosalinine chloride or the like, may give a plaster for topical, ophthalmic use; minute particles, as a dispersant for ophthalmic use is applied directly; when combined with or immersed in an appropriate base or excipient, it gives a soft, long-lasting prescription to be inserted into the space behind the eye-lid.

For the inhalation, the solution or suspension of the compound in a conventional solvent(s) or excipient(s), is used as an aerosol spray. Dry powder placed lungs of the patient.

The dosage of the compound of this invention depends on the kind of the disease, the route of application, the state of the patient, and his/her age, gender and weight. The dosage appropriate for oral use in adults should be around 1-500 mg/day/head, or preferably 10-300 mg/day/head, and the dosage for parenteral application through intravenous, subcutaneous, intramuscular, percutaneous, rectal, intranasal or ophthalmic route, or through airways by inhalation should be around 0.1-100 mg/day/head, or preferably 0.3-30 mg/day/head. The compound should be so prepared as to meet above dosages. When the compound is used as a prophylactic medicine, it can be prepared according to a publicly known method, for example, in such a manner that it can give, when properly administered, a dose sufficiently preventive against a given disease to which it is indicated.

Examples described later demonstrates that the compounds inhibit IgE production in human lymphocytes exposed to antigen non-specific stimuli (IL-4+IL-10 (interleukin 10)+anti CD40Ab (anti CD40 antibody)), at a concentration showing no cytotoxicity. Accordingly, the compound of this invention is beneficial when used as a prophylactic and/or therapeutic drug for allergic diseases such as bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, anaphylactic shock, mite allergy, pollinosis, food allergy, urticaria, ulcerative colitis, eosinophilic gastroenteritis or the like.

Of all the compounds belonging to this invention, those that have more selective inhibitory actions against IgE than against IgG may be more useful as a prophylactic and/or therapeutic drug against allergic diseases because they can more effectively inhibit the untoward immunological reactions involved in the allergic diseases. The "selective action" here means that the compound mitigates or prevents the untoward symptons resulting from IgE production, whereas it does not affect nor scarcely affect the essential immuno responce resulted from IgG production.

Examples described later demonstrates that the compounds inhibit the production or release of chemical mediators, such as histamine and/or LTB₄ (leukotrien B₄) as well as IgE. Accordingly, the compound of this invention is beneficial when B₄) as well as IgE. Accordingly, the compound of this invention is beneficial when used as a prophylactic and/or therapeutic drug against the allergic diseases described above that would result from the release or production of those chemical mediators, as well as from the enhanced production of IgE antibodies.

Futher, examples specified later demonstrated that the compounds interfere with the production of TF in monocytes in human peripheral blood stream induced by lipopolysaccarides (LPS). Accordingly, the compound of this invention is beneficial when used as a prophylactic and/or therapeutic drug against the diseases that would result from the augmented production or activity of TF such as DIC; various thromboses in association with infections, autoimmune diseases including delayed immune response and SLE, various rejection reactions from transplanted organs, glomerular nephritis, viral hepatitis or the like; obstructive arteriosclerosis; cerebral embolism; cerebral infarction; pulmonary embolism; pulmonary infarction; angina pectoris; myocardial infarction; restenosis; Buerger disease; diseases involved in hypertrophic endometritis; and turbidity of an artificial crystalline lens embedded for the treatment of cataract.

The present invention will be detailed below with reference to examples. But the scope of this invention should not be limited only to those examples. The numbers attached at the end of the generic names of the compounds have the same meaning as those in Tables 1-1 to 1-18.

Example 1 Production of 2-(4-(2-naphthyloxy)benzamide)benzoic Acid Methyl Ester (Compound No. 1101) ##STR106##

Under an atmosphere of nitrogen, 29.1 g (0.11 mol) of 4-(2-naphtyloxy)benzoate was suspended in 500 ml of dried methylene chloride, to which were added 15.4 g (0.121 mol) of oxyalyl chloride and then 10 drops of DMF with a pipette. The mixture was stirred at 35 for 2 hours. The reaction product was concentrated with an evaporator, and the residue was dissolved in 300 ml of dry methylene chloride. Under an atmosphere of nitrogen, the solution, while being cooled with ice, was added dropwise to a solution of 16.6 g (0.11 mol) of methyl anthranilate and of 12.3 g (0.121 mol) of triethyl amine in dried methylene chloride (250 ml), and the resultant mixture was stirred for 4 hours in an ice bath, and then stirred overnight at room temperature. Water was added to the reaction mixture, and extracted with methylene chloride twice. The organic phase was washed with a saturated brine, dried with anhydrous sodium sulfate, and the solvent was removed by evaporation. The residue was recrystallized from isopropyl alcohol (1.6 l) to give 40.26 g (92% yield) of 2-(4-(2-naphthyloxy)benzamide)benzoic acid methyl ester. White needle-like crystals.

¹ H-NMR (CDCl₃) (ppm): 3.96(s, 3H), 7.09-7.17(m, 3H), 7.27-7.31(m, 1H), 7.42-7.53(m, 3H), 7.58-7.64(m, 1H), 7.76(d, J=8.5Hz, 1H), 7.84-7.90(m, 2H), 8.03-8.10(m, 3H), 8.93(d, J=8.3Hz, 1H), 12.02(br. s, 1H).

Example 2 Production of 2-(4-(2-naphtyloxy)benzamide)benzoic Acid (Compound No. 1104) ##STR107##

A 40.26 g (0.101 mol) of 2-(4-(2-naphtyloxy)benzamide) benzoic acid methyl ester obtained in Example 1 was dissolved in a mixed solvent of methanol/THF (200 ml/400 ml), to the resulting solution was added 127 ml (0.51 mol) of 4 N lithium hydroxide, and the mixture was stirred overnight at room temperature. To the reaction product was added 5 N hydrochloric acid to give a pH of about 1, and then the mixture was stirred at room temperature for 0.5 hour. Water was added to the resulting solution, and extracted with ethyl acetate twice. The organic phase was washed with brine dried with anhydrous sodium sulfate, and the solvent was removed by evaporation. The residue was recrystallized from isopropyl alcohol (1.3 l) to give 31.23 g (80% yield) of 2-(4-(2-naphthyloxy)benzamide)benzoic acid. White needle-like crystals.

¹ H-NMR (CDCl₃) (ppm): 7.12-7.18(m, 3H), 7.27-7.30(m, 1H), 7.43-7.53(m, 3H), 7.65(dt, J=1.7 and 8.6Hz, 1H), 7.76(d, J=7.6Hz, 1H), 7.85-7.91(m, 2H), 8.03(dd, J=2.0 and 6.9Hz, 2H), 8.14(dd, J=1.7 and 7.9Hz, 1H), 8.96(d, J=7.6Hz, 1H), 11.84(br. s, 1H).

Examples 3-73

In the following examples, the compounds of this invention were prepared from appropriate starting materisl according to the methods described in Examples 1 and 2. Tables 2-1 to 2-13 give the ¹ H-NMR spectrum data of the compounds thus obtained, and their yields. The compound No. in the tables represent the same with those in Tables 1-1 to 1-18. The spectrum data at the end of which (*) is attached are derived from the compounds which are dissolved in DMSO-d₆.

                                      TABLE 2-1                                    __________________________________________________________________________     Example No.                                                                          Compound No.                                                                          .sup.1 H--NMR Spectrum Data(CDCl.sub.3) δ (ppm)                                                    Yield (%)                               __________________________________________________________________________     3     1110   3.94(s, H), 7.11(t, J=11.1Hz, 4H), 7.4-7.7(m, 5                                                          60,                                                  7.72(d, J=8.2 Hz, 1H), 7.90(d, J=8.2 Hz, 1H),                                  8.01(s, 1H), 8.03-8.10(m, 2H), 8.90(d, J=8.5 Hz, 1H),                          12.0(s, 1H).                                                      4     1111   7.00(t, J=7.2Hz, 1H), 7.11(d, J=8.9Hz, 2H),                                                              62                                                   7.18(d, J=8.0Hz, 1H), 7.34(t, J=8.3Hz, 1H),                                    7.50-7.61(m, 3H),7.82(d, J=8.2Hz, 1H), 7.90-8.10(m, 5H),                       8.64(d, J=8.3Hz, 1H), 12.2(br.s, 1H). (*)                         5     1112   3.85(s, 3H), 7.11(t, J=8.3Hz, 1H), 7.20-7.30(m,                                                          66),                                                 7.40-7.65(m, 5H), 7.70-7.90(m, 4H), 8.05(d, J=7.3Hz, 1H),                      8.88(d, J=9.2Hz, 1H), 12.0(s, 1H),                                6     1113   7.01(t, J=7.4Hz, 1H), 7.20-7.40(m, 3H),                                                                  65                                                   7.40-7.55(m, 3H), 7.58(t, J=7.9Hz, 1H), 7.69(s, 1H),                           7.85(d, J=7.6Hz, 1H), 7.92(d, J=1.7Hz, 1H), 7.95(s, 1H),                       8.00(d, J=8.9Hz, 1H), 8.05(d, J=8.6Hz, 1H),                                    8.62(d, J=7.9Hz, 1H), 12.1(br.s, 1H). (*)                         7     1114   3.95(s, 3H), 7.05-7.20(m, 2H), 7.25-7.35(m,                                                              98),                                                 7.45-7.60(m, 3H), 7.70-7.90(m, 2H), 7.93(d, J=1.3Hz, 1H),                      8.11(dt, J=1.3 and 10.0Hz, 1H), 8.70(d, J=2.3Hz, 1H),                          8.87(d, J=7.6Hz, 1H), 12.2(s, 1H).                                8     1116   7.24(t, J=7.2Hz, 1H), 7.34(d, J=8.5Hz, 1H),                                                              34                                                   7.43(dd, J=2.6 and 4.5Hz, 1H), 7.50-7.60(m, 2H),                               7.60-7.70(m, 2H), 7.95(dd, J=8.1 and 14.6Hz, 2H),                              8.06(dd, J=7.6 and 8.0Hz, 2H), 8.20-8.25(m, 2H),                               8.60-8.70(m, 2H), 12.3(s, 1H). (*)                                9     1120   6.95(d, J=8.6Hz, 1H), 7.16(t, J=7.6Hz, 1H),                                                              55                                                   7.43-7.62(m, 4H), 7.73(d, J=2.3Hz, 1H), 7.88-8.07(m, 4H),                      8.55(s, 1H), 8.70(d,J=7.9Hz, 1H), (*)                             __________________________________________________________________________

                                      TABLE 2-2                                    __________________________________________________________________________     Example No.                                                                          Compound No.                                                                          .sup.1 H--NMR Spectrum Data(CDCl.sub.3)                                                                  Yield (%)                               __________________________________________________________________________     10    1121   3.82(s, 3H), 3.98(s, 3H), 6.99-7.03(m, 1H),                                                              1411-                                                7.15(m, 2H), 7.40-7.65(m, 6H), 7.78-8.10(m, 6H), 8.84-                         8.96(m, 3H), 12.10(br.s, 1H), 12.24(br.s, 1H).                    11    1122   7.10(d, J=8.6Hz, 1H), 7.21(t, J=7.9Hz, 1H),                                                              87                                                   7.47-7.55(m, 3H), 7.66-7.69(m, 2H), 7.75(s, 1H),                               7.90-8.12(m, 6H), 8.70-8.78(m, 3H), 12.42(br.s, 2H). (*)          12    1123   3.77(s, 2H), 3.89(s, 3H), 7.05-7.11(m, 3H),                                                              6527-                                                7.57(m, 7H), 7.69(d, J=7.6Hz, 1H), 7.82(d, J=8.6Hz, 2H),                       8.01(dd, J=1.7 and 7.9 Hz, 1H), 8.73(d, J=8.6Hz, 1H),                          11.10(br.s, 1H).                                                  13    1126   3.80(s, 2H), 7.04(t, J=7.6Hz, 1H), 7.09-7.14(m,                                                          81),                                                 7.21-7.29(m, 2H), 7.34-7.45(m, 4H), 7.54-7.65(m, 2H),                          7.76(d, J=8.6Hz, 2H), 8.07(dd, J=1.7 and 7.9Hz, 1H),                           8.76(dd, J=1.0 and 8.6Hz, 1H), 10.74(br.s, 1H),                   14    1145   2.78(t, J=7.3Hz, 2H), 3.09(t, J=7.3Hz, 2H),                                                              90                                                   3.92(s, 3H), 6.99-7.03(m, 2H), 7.05-7.12(m, 1H),                               7.22-7.27(m, 4H), 7.41(dquint, J=1.3 and 6.9Hz, 2H),                           7.55(dt, J=1.7 and 6.9Hz, 1H), 7.67(d, J=7.6Hz, 1H),                           7.81(d, J=8.6Hz, 2H), 8.03(dd, J=1.7 and 7.9Hz, 1H),                           8.73(dd, J=1.0 and 8.6Hz, 1H), 11.09(br.s, 1H),                   15    1146   2.78(t, J=7.9Hz, 2H). 3.09(t, J=7.9Hz, 2H),                                                              69                                                   6.97-7.02(m, 2H), 7.12(dt, J=1.0 and 7.3Hz, 1H),                               7.20-7.27(m, 4H), 7.41(dquint, J=1.3 and 6.9Hz, 2H),                           7.57-7.68(m, 2H), 7.80(d, J=8.9Hz, 2H),                                        8.10(dd, J=1.7 and 7.9Hz, 1H),                                                 8.76(dd, J=1.0 and 8.6Hz, 1H), 10.87(br.s,                        __________________________________________________________________________                  1H).                                                         

                                      TABLE 2-3                                    __________________________________________________________________________     Example No.                                                                          Compound No.                                                                          .sup.1 H--NMR Spectrum Data(CDCl.sub.3) δ (ppm)                                                    Yield (%)                               __________________________________________________________________________     16    1147   3.96(s, 3H), 6.55(d, J=15.5Hz, 1H), 7.04-7.13(m,                                                         85),                                          (trans-)                                                                              7.25-7.31(m, 1H), 7.41-7.52(m, 3H), 7.56-7.62(m, 3H),                          7.72-7.78(m, 2H), 7.83-7.89(m, 2H),                                            8.06(dd, J=1.7 and 7.9Hz, 1H),                                                 8.88(dd, J=1.0 and 8.6Hz, 1H), 11.35(br.s, 1H).                   17    1148   6.54(d, J=15.5Hz, 1H), 7.05-7.08(m, 2H), 7.11-7.17(m,                                                    84),                                          (trans-)                                                                              7.24-7.29(m, 1H), 7.40-7.52(m, 3H), 7.56-7.65(m, 3H)                           7.67-7.88(m, 4H), 8.15(dd, J=1.7 and 8.2Hz, 1H)                                8.91(dd, J=1.0 and 8.6Hz, 1H), 11.16(br.s, 1H).                   18    3101   3.94(s, 3H), 7.11(t, J=7.3Hz, 1H). 7.35(d, J=8.3Hz,                                                      83),                                                 7.49-7.63(m, 4H), 7.79-7.89(m, 3H), 7.94(d, J=8.6Hz, 2H),                      8.04(d, J=1.3Hz, 1H), 8.07(dd, J=1.7 and 8.3Hz, 1H),                           8.91(d, J=7.9Hz, 1H), 12.02(br.s, 1H),                            19    3102   7.15(t, J=7.6Hz, 1H), 7.34(d, J=8.6Hz, 2H),                                                              91                                                   7.49-7.65(m, 4H), 7.80-7.92(m, 5H), 8.04(s, 1H),                               8.13(dd, J=2.0 and 8.3Hz, 1H), 8.93 (d, J=8.3Hz, 1H),                          11.84(br.s, 1H).                                                  __________________________________________________________________________

                                      TABLE 2-4                                    __________________________________________________________________________     Example No.                                                                          Compound No.                                                                          .sup.1 H--NMR Spectrum Data(CDCl.sub.3) δ (ppm)                                                    Yield (%)                               __________________________________________________________________________     20    1203   3.93(s, 3H), 3.95(s, 3H), 7.09-7.24(m, 6H), 7.42(d,                                                      452Hz,                                               1H), 7.61(t, J=7Hz, 1H), 7.67(d, J=10Hz, 1H), 7.78(d,                          J=9Hz, 1H), 8.04(d, J=9Hz, 2H), 8.08(dd, J=2 and 8Hz,                          1H), 8.93(d, J=9Hz, 1H), 12.01(br.s, 1H).                         21    1204   3.98(s, 3H), 7.08-7.26(m, 6H), 7.42(d, J=2Hz, 1H),                                                       6765-                                                7.73(m, 3H), 8.00-8.26(m, 3H), 8.96(d, J=9Hz, 1H), 11.87                       (br.s, 1H),                                                       22    1205   3.95(s, 3H), 5.20(s.2H), 7.00-7.15(m, 2H),                                                               5620-                                                7.30(m, 4H), 7.35-7.45(m, 4H), 7.49(d, J=1.0Hz, 2H),                           7.50-7.80(m, 1H),                                                              7.60-7.70(m, 1H), 7.76(d, J=8.9Hz, 1H), 8.04(dd, J=2.0 and                     9.9Hz, 2H), 8.10(d, J=1.7Hz, 1H), 8.90(dd, J=1.0 and 9.5                       Hz, 1H), 12.0(br.s, 1H),                                          23    1206   5.23(s, 2H), 7.17(d, J=8.7Hz, 2H), 7.20-7.45(m, 6H),                                                     8245-                                                7.60(m, 4H), 7.65(t, J=7.5Hz, 1H), 7.82(d, J=8.9Hz,                            1H), 7.90(d, J=8.9Hz, 1H), 7.98(d, J=8.9Hz, 2H), 8.05                          (dd, J=1.7 and 8.9Hz, 1H), 8.72(d, J=8.5Hz, 1H), 12.2(br.                      s, 1H), 13.7(br.s, 1H). (*)                                       24    1209   1.40(s, 9H), 3.76(s.2H), 3.88(s, 3H), 7.06(d,                                                            648.6Hz,                                             3H), 7.09-7.23(m, 2H), 7.32-7.38(m, 4H), 7.53(t, J=7.3Hz,                      1H), 7.60(d, J=8.9Hz, 1H), 7.72(d, J=8.9Hz, 1H),                               8.01(dd, J=1.7 and 7.9Hz, 1H), 8.73(dd, J=1.0 and 8.6Hz,                       1H), 11.08(br.s, 1H).                                             25    1210   1.40(s, 9H), 3.79(s, 2H), 7.03-7.23(m, 4H),                                                              9226-                                                7.27(m, 1H), 7.33-7.36(m, 4H), 7.56(t, J=8.9Hz, 2H),                           7.69(d, J=8.9Hz,                                                               1H), 8.08(d, J=8.3Hz, 1H), 8.76(d, J=8.2Hz, 1H), 10.79                         (br.s, 1H).                                                       __________________________________________________________________________

                                      TABLE 2-5                                    __________________________________________________________________________     Example No.                                                                          Compound No.                                                                          .sup.1 H--NMR Spectrum Data(CDCl.sub.3) δ (ppm)                                                    Yield (%)                               __________________________________________________________________________     26    1211   1.3-1.5(m, 3H), 1.5-1.65(m, 3H), 1.75-1.9(m,                                                             71),                                                 2.0-2.15(m, 2H), 3.75(s, 2H), 3.88(s, 3H), 4.33-4.42(m, 1H),                   7.02-7.15(m, 5H), 7.20-7.24(m, 1H), 7.31-                                      7.37(m, 3H), 7.53(dt, J=                                                       1.6 and 8.6Hz, 1H), 7.60(d, J=8.6Hz, 1H), 7.68(d,                              J=8.9Hz, 1H), 8.00(dd, J=1.7 and 8.2Hz, 1H),                                   8.72(dd, J=1.0 and 8.6Hz,                                                      1H), 11.07(br.s, 1H).                                             27    1212   1.25-1.65(m, 6H), 1.75-1.9(m, 2H), 2.0-2.15(m, 2H),                                                      8678(s,                                              2H), 4.31-4.40(m, 1H), 7.01-7.13(m, 6H), 7.18(dd, J=1.6 and                    8.9Hz, 1H), 7.33(d, J=8.6Hz, 2H), 7.55(d, J=9.9Hz, 2H),                        7.63(d, J=8.9Hz, 1H), 8.06(dd, J=1.7 and 7.9Hz, 1H), 8.75                      (d, J=8.6Hz, 1H), 10.76(br.s, 1H),                                28    1213   0.89(t, J=6.9Hz, 3H), 1.2-1.45(m, 8H), 1.45-1.65(m,                                                      51),                                                 1.84(quint, J=6.6Hz, 2H), 3.75(s, 2H), 3.88(s, 3H), 4.06                       (t, J=6.6Hz, 2H), 7.03-7.15(m, 5H), 7.21-7.25(m, 1H), 7.32-                    7.37(m, 3H), 7.53(t, J=7.3Hz, 1H), 7.60(dd, J=2.3 and 7.6                      Hz, 1H), 7.69(d, J=8.9Hz, 1H), 8.01(dd, J=1.7 and 7.9Hz,                       1H), 8.73(dd, J=1.0 and 8.3Hz, 1H), 11.08(br.s, 1H).              29    1214   0.85(t, J=6.6Hz, 3H), 1.25-1.55(m, 10H), 1.76(quint,                                                     866.6                                                Hz, 2H), 3.75(s, 2H), 4.05(t, J=6.6Hz, 2H), 7.01(d, J=8.6                      Hz, 2H), 7.10-7.15(m, 2H), 7.23(dd, J=2.3 and 8.9Hz, 1H),                      7.32-7.38(m, 4H), 7.57(t, J=7.3Hz, 1H), 7.72(d, J=9.3Hz,                       1H), 7.83(d, J=8.9Hz, 1H), 7.95(dd, J=1.7 and 7.9Hz, 1H),                      8.50(d, J=8.6Hz, 1H), 11.16(br.s, 1H), 13.57(br.s, 1H). (*)       30    1215   2.05(s, 4H), 3.75(s, 2H), 3.89(s, 3H), 4.07(t,                                                           705.6Hz,                                             2H), 4.15(t, J=5.6Hz, 2H), 6.87-6.97(m, 3H), 7.02-7.18(m,                      5H), 7.21-7.37(m, 6H), 7.50-7.57(m, 1H), 7.60(d, J=9.6Hz,                      1H), 7.69(d, J=8.9Hz, 1H), 8.01(dd, J=1.6 and 7.9Hz, 1H),                      8.73(dd, J=1.0 and 8.6Hz, 1H), 11.08(br.s,                        __________________________________________________________________________                  1H).                                                         

                                      TABLE 2-6                                    __________________________________________________________________________     Example No.                                                                          Compound No.                                                                          .sup.1 H--NMR Spectrum Data(CDCl.sub.3) δ (ppm)                                                    Yield (%)                               __________________________________________________________________________     31    1216   1.8-2.0(m, 4H), 3.72(s, 2H), 4.04(t, J=5.6Hz, 2H),                                                       7714                                                 (t, J=5.6Hz, 2H), 6.88-6.94(m, 3H), 7.01(d, J=8.6Hz, 2H),                      7.11-7.16(m, 2H), 7.21-7.30(m, 3H), 7.35-7.38(m, 4H),                          7.53-7.55(m, 1H), 7.73(d, J=8.9Hz, 1H),                                        7.821(d, J=8.9Hz, 1H),                                                         7.94(dd, J=1.7 and 7.9Hz, 1H), 8.49(d, J=8.6Hz, 1H). (*)          32    1217   3.75(s, 2H), 3.89(s, 3H), 4.65(d, J=6.3Hz, 2H),                                                          4732(d,                                              J=10.6Hz, 1H), 5.47(d, J=17.5Hz, 1H), 6.05-6.20(m, 1H),                        7.03-7.23(m, 6H), 7.32-7.37(m, 3H), 7.53(t, J=7.3Hz, 1H),                      7.61(d, J=8.6Hz, 1H), 7.70(d, J=8.9Hz, 1H), 8.01(dd, J=                        1.3 and 7.9Hz, 1H), 8.73(d, J=8.6Hz, 1H), 11.08(br.s, 1H),        33    1218   3.74(s.2H), 4.66(d, J=5.3Hz, 2H), 5.28(dd, J=1.3                                                         62d                                                  10.6Hz, 1H), 5.44(dd, J=1.7 and 17.5Hz, 1H), 6.03-6.15(m,                      1H), 7.02(d, J=8.6Hz, 2H), 7.09-7.26(m, 3H), 7.35-7.39(m,                      4H), 7.54-7.59(m, 1H), 7.74(d, J=8.9Hz, 1H), 7.83(d, J=                        8.9Hz, 1H), 7.95(dd, J=1.3 and 8.2Hz, 1H), 8.50(d, J=8.6                       Hz, 1H), 11.15(br.s, 1H), 13.56(br.s, 1H). (*)                    34    1219   1.95(quint, J=6.6Hz, 2H), 2.28(q, J=6.9Hz, 2H),                                                          5475(s,                                              2H), 3.88(s, 3H), 4.08(t, J=6.6Hz, 2H), 5.02(dd, J=2.0                         and 10.3Hz, 1H), 5.09(dd, J=2.0 and 17.2Hz, 1H), 5.81-5.96                     (m, 1H), 7.03-7.16(m, 5H), 7.21-7.25(m, 1H),                                   7.32-7.38(m, 3H),                                                              7.53(dt, J=1.7 and 7.3Hz, 1H), 7.60(d, J=9.6Hz, 1H),                           7.69(d, J=8.9Hz, 1H), 8.00(dd, J=1.7 and 7.9Hz, 1H), 8.72                      (dd, J=1.3 and 8.6Hz, 1H), 11.08(br.s, 1H).                       35    1220   1.87(quint, J=6.3Hz, 2H), 2.23(q, J=6.6Hz, 2H),                                                          8976(s,                                              2H), 4.08(t, J=6.6Hz, 2H), 5.01(d, J=10.2Hz, 1H), 5.08                         (dd, J=2.0 and 17.2Hz, 1H), 5.82-5.97(m, 1H), 7.03(d, J=8.6                    Hz, 2H), 7.11-7.17(m, 2H), 7.25(dd, J=2.6 and 8.9Hz, 1H),                      7.33-7.40(m, 4H), 7.58(t, J=8.6Hz, 1H), 7.74(d, J=8.9Hz,                       1H), 7.85(d, J=8.9Hz, 1H), 7.96(dd, J=1.7 and 8.3Hz, 1H),                      8.51(dd, J=8.3Hz, 1H), 11.14(br.s, 1H), 13.54(br.s, 1H).          __________________________________________________________________________                  (*)                                                          

                                      TABLE 2-7                                    __________________________________________________________________________     Example No.                                                                          Compound No.                                                                          .sup.1 H--NMR Spectrum Data(CDCl.sub.3) δ (ppm)                                                    Yield (%)                               __________________________________________________________________________     36    1221   1.61(s, 3H), 1.67(s, 3H), 1.78(s, 3H), 2.08-2.14(m, 4H),                       3.75                      37                                                   (s, 2H), 3.88(s, 3H), 4.64(d, J=6.6Hz, 2H), 5.11(br., 1H),                     5.56(t, J=7.6Hz, 1H), 7.03-7.07(m, 3H), 7.10-7.17(m, 2H),                      7.21-7.25(m, 1H), 7.32-7.37(m, 3H), 7.53(t, J=8.6Hz, 1H),                      7.60(d, J=9.6Hz, 1H), 7.70(d, J=8.9Hz, 1H), 8.01(dd, J=                        1.7 and 7.9Hz, 1H), 8.72(d,m J=8.3Hz, 1H), 11.07(br.s, 1H).       37    1222   1.57(s, 3H), 1.61(s, 3H), 1.74(s, 3H), 2.02-2.13(m, 4H),                       3.76                      66                                                   (s, 2H), 4.65(d, J=6.3Hz, 2H), 5.08(br., 1H), 5.49(t, J=                       6.9Hz, 1H), 7.03(d, J=8.6Hz, 2H), 7.11-7.16(m, 2H), 7.25                       (dd, J=2.3 and 8.9Hz, 1H), 7.35-7.40(m, 4H), 7.58(t, J=8.6                     Hz, 1H), 7.73(d, J=8.9Hz, 1H), 7.83(d, J=8.9Hz, 1H), 7.96                      (d, J=1.7 and 7.9Hz, 1H), 8.51(d, J=7.9Hz, 1H), 11.14(br.                      s, 1H), 13.50(br.s, 1H). (*)                                      38    1223   3.75(s, 2H), 3.88(s, 3H), 5.17(s, 2H), 7.02-7.11(m,                                                      72),                                                 7.20-7.26(m, 3H), 7.32-7.56(m, 9H), 7.62(d, J=9.6Hz, 1H),                      7.70(d, J=8.9Hz, 1H), 8.01(dd, J=1.7 and 8.2Hz, 1H), 8.73                      (dd, J=1.0 and 8.3Hz, 1H), 11.08(br.s, 1H)                        39    1224   3.74(s, 2H), 5.20(s, 2H), 7.02(d,J=8.6Hz, 2H),                                                           7812(t,                                              J=7.3Hz, 1H), 7.20-7.27(m, 2H), 7.30-7.58(m, 10H), 7.75                        (d, J=8.9Hz, 1H), 7.83(d, J=8.9Hz, 1H), 7.95(dd, J=1.3                         and 7.9Hz, 1H), 8.50(d, J=1.9Hz, 1H). (*)                         40    1225   2.17(quint, J=6.3Hz, 2H), 2.86(t, J=7.3Hz, 2H),                                                          5975(s,                                              2H), 3.89(s, 3H), 4.07(t, J=6.3Hz, 2H), 7.03-7.11(m, 2H),                      7.05(d, J=8.6Hz, 2H), 7.13-7.38(m, 10H), 7.54(dt, J=1.7                        and 7.3Hz, 1H), 7.61(d, J=8.9Hz, 1H), 7.67(d, J=8.9Hz,                         1H), 8.00(dd, J=1.7 and 7.9Hz, 1H), 8.73(dd, J=1.0 and 8.6                     Hz, 1H), 11.08(br.s, 1H).                                         __________________________________________________________________________

                                      TABLE 2-8                                    __________________________________________________________________________     Example No.                                                                          Compound No.                                                                          .sup.1 H--NMR Spectrum Data(CDCl.sub.3) δ (ppm)                                                    Yield (%)                               __________________________________________________________________________     41    1226   2.03-2.14(m, 2H), 2.79(t, J=7.3Hz, 2H), 3.76(s, 2H),                                                     8607                                                 (t, J=6.3Hz. 2H), 7.03(d, J=8.3Hz, 2H), 7.11-7.40(m, 12H),                     7.52-7.60(m, 1H), 7.75(d, J=8.9Hz, 1H), 7.83(d, J=9.2Hz,                       1H), 7.96(dd, J=1.7 and 7.9Hz, 1H), 8.51(d, J=8.6Hz, 1H),                      11.18(br.s, 1H). (*)                                              42    1227   3.75(s, 2H), 3.88(s, 3H), 5.34(s, 2H), 7.03-7.10(m,                                                      23),                                                 7.22-7.28(m, 3H), 7.33-7.37(m, 3H), 7.46-7.71(m, 6Hz,                          7.84-7.90(m, 3H), 7.94(s, 1H), 8.00(dd, J=1.7 and                              7.9Hz, 1H), 8.72(d, J=8.6Hz, 1H), 11.07(br, s, 1H).               43    1228   3.76(s, 2H), 5,39(s, 2H), 7.03(d, J=8.6Hz, 2H), 7.14(d,                                                  30                                                   7.9Hz, 1H), 7.24-7.30(m, 2H), 7.38(d, J=8.6Hz, 3H), 7.51-                      7.66(m, 5H), 7.78(d, J=9.2Hz, 1H), 7.86(d, J=8.9Hz,                            1H), 7.93-7.98(m, 4H), 8.05(s, 1H), 8.51(d, J=7.9Hz, 1H),                      11.17(br.s, 1H), 13.56(br.s, 1H). (*)                             44    1149   1.64(d, J=7.3Hz, 3H), 3.75-3.83 (m, 4H), 3.89(s, 3H),                                                    6503-                                                7.09(m, 3H), 7.24-7.28(m, 1H), 7.33-7.56(m, 6H),                               7.69(dd, J=                                                                    1.7 and 7.6Hz, 1H), 7.81(d, J=8.9Hz, 2H), 8.00(dd, J=1.7 and                   7.9Hz, 1H), 8.74(dd, J=1.0 and 8.6Hz, 1H), 11.14(br.s, 1H),       45    1150   1.48(d, J=6.9Hz, 3H), 3.88(q, J=6.9Hz, 1H),                                                              7104-7.14(m,                                         3H), 7.28(dd, J=2.3 and 8.9Hz, 1H), 7.39-7.59(m, 6H), 7.80                     (d, J=7.6Hz, 1H), 7.90(dd, J=1.3 and 7.6Hz, 1H), 7.95(d,                       J=8.2Hz, 2H), 8.52(d, J=7.6Hz, 1H), 11.28(br.s, 1H). (*)          46    1151   1.73(s, 6H), 3.84(s, 3H), 7.07(d, J=8.9Hz, 3H),                                                          8825-7.29                                            (m, 1H), 7.34-7.56(m, 6H), 7.68(d, J=7.9Hz, 1H), 7.81(d, J=                    8.9Hz, 2H), 7.99(dd, J=1.7 and 7.9Hz, 1H), 8.76(dd, J=1.0                      and 7.6Hz, 1H), 10.95(br.s, 1H).                                  __________________________________________________________________________

                                      TABLE 2-9                                    __________________________________________________________________________     Example No.                                                                          Compound No.                                                                          .sup.1 H--NMR Spectrum Data(CDCl.sub.3) δ (ppm)                                                    Yield (%)                               __________________________________________________________________________     47    1152   1.61(s, 6H), 7.07(d, J=8.6Hz, 2H), 7.11(t, J=7.3Hz,                                                      85),                                                 7.28(dd, J=1.6 and 8.9Hz, 1H), 7.40-7.52(m, 5H), 7.58(dt, J=                   1.7 and 6.9Hz, 1H), 7.80(d, J=7.9Hz, 1H), 7.90-7.97(m, 3H),                    8.62(d, J=8.6Hz, 1H), 11.25(br.s, 1H), 13.62(br.s, 1H). (*)       48    1153   2.36(s, 3H), 3.88(s, 3H), 7.14(d, J=8.9Hz, 2H),                                                          5018-7.24                                            (m, 1H), 7.27-7.31(m, 1H), 7.42-7.53(m, 4H), 7.76(d, J=7.3                     Hz, 1H), 7.84-7.91(m, 3H), 8.01-8.04(m, 2H),                                   10.18(br.s, 1H).                                                  49    1154   2.36(s, 3H), 7.13(d, J=8.6Hz, 2H), 7.21-7.30(m, 2H),                                                     7143                                                 7.55(m, 4H), 7.76(d, J=7.3Hz, 1H), 7.85-7.94(m, 3H), 8.00                      (d, J=8.9Hz, 2H), 9.98(br.s, 1H).                                 50    1155   3.80(s, 2H), 3.95(s, 3H), 7.10(d, J=6Hz, 2H),                                                            5326-7.46                                            (m, 6H), 7.69(d, J=9Hz, 1H), 7.82(d, J=9Hz, 2H), 7.87                          (dd, J=2 and 9Hz, 1H), 8.17(d, J=9Hz, 1H), 9.64(d, J=                          2Hz, 1H), 11.12(br.s, 1H).                                        51    1156   3.83(s, 2H), 7.08(d, J=8Hz, 2H), 7.29(dd, J=2 and                                                        69z,                                                 1H), 7.39-7.48(m, 5H), 7.81(d, J=8Hz, 1H), 7.89-7.97(m,                        3H), 8.19(d, J=9Hz, 1H), 9.37(d, J=2Hz, 1H), 11.65                             (br.s, 1H). (*)                                                   52    1157   3.77(s, 2H), 3.88(s, 3H), 6.77(d, J=2 and 7Hz, 1H),                                                      6208                                                 (d, J=9Hz, 2H), 7.32-7.48(m, 6H), 7.69(d, J=8Hz, 1H),                          7.82(d, J=9Hz, 2H), 8.02(dd, J=6 and 9Hz, 1H), 8.57(dd,                        J=3 and 12Hz, 1H), 11.25(br.s, 1H).                               53    1158   3.78(s, 2H), 6.68(m, 1H), 7.11(d, J=9Hz, 2H), 7.20(dd,                                                   82                                                   2 and 9Hz, 2H), 7.32-7.42(m, 4H), 7.61(d, J=8Hz, 1H),                          7.75(d, J=9Hz, 2H), 8.05(t, J=6Hz, 1H), 8.56(dd, J=2                           and 12Hz, 1H), 10.88(br.s, 1H).                                   __________________________________________________________________________

                                      TABLE 2-10                                   __________________________________________________________________________     Example No.                                                                          Compound No.                                                                          .sup.1 H--NMR Spectrum Data(CDCl.sub.3) δ (ppm)                                                    Yield (%)                               __________________________________________________________________________     54    1159   3.76(s, 2H), 3.89(s, 3H), 7.09(d, J=9Hz, 2H),                                                            6026-7.45                                            (m, 7H), 7.68(dd, J=3 and 9Hz, 2H), 7.82(d, J=9Hz, 2H),                        8.74(dd, J=5 and 9Hz, 1H), 10.91(br.s, 1H).                       55    1160   3.75(s, 2H), 7.07(d, J=9Hz, 2H), 7.29(dd, J=3 and                                                        85z,                                                 1H), 7.38-7.48(m, 6H), 7.54(dd, J=3 and 9Hz, 1H), 7.82(d,                      J=8Hz, 1H), 7.88-7.91(m, 1H), 7.95(d, J=9Hz, 1H), 8.52                         (d, J=9Hz, 1H), 11.99(br.s, 1H). (*)                              56    1161   3.76(s, 2H), 3.89(s, 3H), 7.09(d, J=9Hz, 2H),                                                            9525-7.51                                            (m, 7H), 7.69(d, J=8Hz, 1H), 7.82(d, J=9Hz, 2H),                               7.98(d, J=3Hz, 1H), 8.73(d, J=9Hz, 1H), 10.99(br.s, 1H).          57    1162   3.71(s, 2H), 7.06(d, J=9Hz, 2H), 7.29(dd, J=3 and                                                        81z,                                                 2H), 7.38-7.50(m, 5H), 7.67(dd, J=3 and 10Hz, 1H), 7.82(d,                     J=8Hz, 1H), 7.89(d, J=8Hz, 1H), 7.95(d, J=9Hz, 1H),                            8.50(dd, J=5 and 9Hz, 1H), 12.3(br.s, 1H). (*)                    58    1163   2.41(s, 3H), 3.73(s, 2H), 3.81(s, 3H), 6.96(d,                                                           388Hz,                                               1H), 7.10(d, J=9Hz, 2H), 7.27-7.46(m, 7H), 7.70(d, J=                          7Hz, 1H), 7.82(dd, J=3 and 9Hz, 2H), 8.23(d, J=9Hz, 1H),                       9.39(br.s, 1H).                                                   59    1164   2.37(s, 3H), 3.65(s, 2H), 6.96(d, J=7Hz, 1H), 7.04(d,                                                    75                                                   8Hz, 2H), 7.17-7.49(m, 7H), 7.73(d, J=8Hz, 1H), 7.81(d, J=                     8Hz, 1H), 7.90(d, J=8Hz, 1H), 7.94(d, J=8Hz, 1H),                              10.57(br.s, 1H). (*)                                              __________________________________________________________________________

                                      TABLE 2-11                                   __________________________________________________________________________     Example No.                                                                          Compound No.                                                                          .sup.1 H-NMR Spectrum Data (CDCl.sub.3) δ (ppm)                                                     Yield (%)                              __________________________________________________________________________     60    4101   3.92(s, 3H), 4.20(s, 2H), 7.09(t, J=7.3Hz,                                                                100                                                 7.22-7.48(m, 5H), 7.56-7.64(m, 2H), 7.76-7.82(m, 3H),                          7.99(d, J=7.9Hz, 2H), 8.06(dd, J=1.3 and 8.3Hz, 1H),                           8.93(d, J=8.6Hz, 1H), 12.01(br, s, 1H).                           61    4103   4.22(s, 2H), 7.15(t, J=8.3Hz, 1H), 7.24-7.50(m,                                                           79),                                                7.63-7.69(m, 2H), 7.77-7.83(m, 3H), 7.96(d, J=8.6Hz, 2H),                      8.14(dd, J=1.7 and 7.9Hz, 1H), 8.96(d, J=7.9Hz, 1H),                           11.80(br, s, 1H).                                                 62    5101   3.95(s, 3H), 5.26(s, 2H), 7.09-7.15(m, 1H), 7.20-7.27(m,                       2H),                       60                                                  7.34(dt, J=1.3 and 7.9Hz, 1H),                                                 7.44(dt, J=1.3 and 7.9Hz, 1H), 7.57-7.65(m, 3H),                               7.72(d, J=8.3Hz, 1H), 7.77(d, J=8.6Hz, 2H),                                    8.06-8.11(m, 3H), 8.94(d, J=8.3Hz, 1H), 12.07(br, s, 1H).         63    5102   5.28(s, 2H), 7.17-7.45(m, 5H), 7.63-7.80(m,                                                               85),                                                8.07(d, J=8.6Hz, 2H), 8.15(dd, J=1.7 and 7.9Hz, 1H),                           8.95-8.99(m, 1H), 11.90(s, 1H).                                   __________________________________________________________________________

                                      TABLE 2-12                                   __________________________________________________________________________     Example No.                                                                          Compound No.                                                                          .sup.1 H-NMR Spectrum Data (CDCl.sub.3) δ (ppm)                                                   Yield (%)                                __________________________________________________________________________     64    5103   3.78(s, 2H), 3.85(s, 3H), 5.18(s, 2H),                                                                  65                                                    7.06(t, J=7.9Hz, 1H), 7.19-7.23(m, 2H), 7.30-7.36(m, 1H),                      7.40-7.55(m, 6H), 7.70-7.78(m, 3H),                                            7.99(dd, J=1.7 and 8.2Hz, 1H), 8.70(d, J=8.3Hz, 1H),                           11.10(br, s, 1H).                                                 65    5104   3.81(s, 2H), 5.19(s, 2H), 6.98(t, J=7.9Hz,                                                              76),                                                  7.16-7.21(m, 2H), 7.30-7.45(m, 4H), 7.50-7.56(m, 3H),                          7.65-7.77(m, 3H), 8.03(dd, J=1.7 and 7.9Hz, 1H),                               8.74(dd, J=1.0 and 8.6Hz, 1H), 10.68(br, s, 1H).                  66    6101   3.96(s, 3H), 4.26(s, 2H), 7.12(dt, J=1.3 and 8.3Hz,                                                     87),                                                  7.38-7.50(m, 5H), 7.60(dt, J=1.7 and 8.6Hz, 1H),                               7.69-7.80(m, 4H), 7.95(d, J=2.0Hz, 1H),                                        7.98(d, J=1.7Hz, 1H), 8.08(dd, J=1.7 and 7.9Hz, 1H),                           8.92(d, J=8.6Hz, 1H), 12.01(br, s, 1H).                           67    6102   4.26(s, 2H), 7.15(t-like, 1H), 7.29-7.47(m,                                                             22),                                                  7.63-7.80(m, 5H), 7.92-7.95(m, 2H),                                            8.13(dd, J=1.7 and 7.9Hz, 1H), 8.93-8.96(m, 1H),                               11.84(s, 1H).                                                     68    7101   3.99(s, 3H), 7.17(t, J=8.6Hz, 1H), 7.55-7.68(m,                                                         79),                                                  7.92-8.02(m, 6H), 8.12(dd, J=1.3 and 7.9Hz, 1H),                               8.18-8.28(m, 3H), 8.96(d, J=8.6Hz, 1H), 12.21(br, s, 1H).         69    7102   7.18-7.24(m, 1H), 7.58-7.70(m, 3H), 7.92-8.01(m,                                                        79),                                                  8.17(d, J=8.6Hz, 3H), 8.28(s, 1H), 8.99(d, J=8.3Hz, 1H),                       12.04(br, s, 1H).                                                 __________________________________________________________________________

                                      TABLE 2-13                                   __________________________________________________________________________     Example No.                                                                          Compound No.                                                                               .sup.1 H-NMR Spectrum Data (CDCl.sub.3) δ                                                      Yield (%)                              __________________________________________________________________________     70    7103   3.96(s, 3H), 7.15(t, J=7.3Hz, 1H), 7.50-7.70(m,                                                           90),                                                7.90-8.20(m, 8H), 8.92(d, J=7.6Hz, 1H), 12.1(s, 1H).              71    7104   7.24(t, J=7.3Hz, 1H), 7.50-7.70(m, 5H), 7.95(d, J=8.3Hz,                       2H),                       69                                                  8.00-8.10(m, 5H), 8.11(d, J=1.7Hz, 1H), 8.68(d, J=8.3Hz,                       1H),                                                                           12.3(s, 1H), 13.8(br, s, 1H). (*)                                 72    8101   3.45(s, 3H), 3.94(s, 3H), 5.47(s, 1H),                                                                    100                                                 7.11(t, J=7.3Hz, 1H), 7.41-7.52(m, 3H), 7.55-7.64(m, 3H),                      7.73-7.85(m, 4H), 8.00-8.09(m, 3H), 8.92(d, J=8.3Hz, 1H),                      12.01(br, s, 1H).                                                 73    8102   3.45(s, 3H), 5.48(s, 1H), 7.15(t, J=7.3Hz,                                                                80),                                                7.40-7.68(m, 6H), 7.80-7.85(m, 4H), 8.00(d, J=8.2Hz, 2H),                      8.14(d, J=7.9Hz, 1H), 8.95(d, J=8.6Hz, 1H),                                    11.82(br, s, 1H).                                                 __________________________________________________________________________

Example 74 Production of N-phenyl-4-(2-naphtyloxy)benzamide (Compound No. 1105) ##STR108##

Under an atmosphere of nitrogen, 53 mg (0.20 mmol) of 4-(2-naphtyloxy) benzoic acid was suspended in 5 ml of dried methylene chloride, to which were added 56 mg (0.44 mmol) of oxyalyl chloride and then 1 drop of DMF with a pipette. The mixture was stirred at 35° C. for 1.5 hours. The reaction mixture was concentrated with an evaporator, and the residue was dissolved in 5 ml of dried methylene chloride. Under an atmosphere of nitrogen, the solution, while being cooled with ice, was added dropwise to a solution of 19 mg (0.20 mmol) of aniline and of 22 mg (0.22 mmol) of triethyl amine in dried methylene chloride (5 ml), and the resulting mixture was stirred for 4 hours in an ice bath, and then stirred overnight at room temperature. Water was added to the reaction mixture, and extracted with methylene chloride twice. The organic phase was washed with brine dried with anhydrous sodium sulfate, and the solvent was removed by evaporation. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to give 27 mg (40% yield) of N-phenyl-(4-(2-naphthyloxy)benzamide). White solid.

¹ H-NMR (CDCl₃) δ (ppm): 7.10-7.18(m, 3H), 7.24-7.29(m, 2H), 7.34-7.53(m, 4H), 7.62-7.65(m, 2H), 7.74-7.77(m, 2H), 7.86-7.90(m, 3H).

Example 75 Production of 2-(4-(2-naphtyloxy)benzamide)phenol (Compound No. 1106) ##STR109##

Under an atmosphere of nitrogen, 144 mg (0.54 mmol) of 4-(2-naphtyloxy)benzoic acid was suspended in 5 ml of dried methylene chloride, to which were added 76 mg (0.60 mmol) of oxyalyl chloride and then 1 drop of DMF with a pipette. The mixture was stirred at 35° C. for 1.5 hours. The reaction mixture was concentrated with an evaporator, and the residue was dissolved in 9 ml of dried methylene chloride. Under an atmosphere of nitrogen, the solution, while being cooled with ice, was added dropwise to a solution of 59 mg (0.54 mmol) of o-aminophenol and of 3 ml of dried pyridine in dried methylene chloride (6 ml), and the resulting mixture was stirred for 1.5 hours in an ice bath, and then stirred at room temperature for three days. Water was added to the reaction mixture, and extracted with methylene chloride twice. The organic phase was washed with brine, and dried with anhydrous sodium sulfate, and the solvent was removed by evaporation. The residue was purified through silica gel chromatography (hexane:ethyl acetate=20:1 to 10:1) to give 147 mg (76% yield) of 2-(4-(2-naphthyloxy)benzamide)phenol. White solid.

¹ H-NMR (CDCl₃) δ (ppm): 6.89-6.96(m, 1H), 7.03-7.23(m, 5H), 7.28-7.29(m, 1H), 7.44-7.76(m, 3H) , 7.78-7.79(d, J=1.7Hz, 1H), 7.85-7.94(m, 4H), 8.67(s, 1H).

Example 76 Production of 2-(4-(2-naphtyloxy)benzamide)benzenesulfonamide (Compound No. 1107) ##STR110##

Under an atmosphere of nitrogen, 132 mg (0.5 mmol) of 4-(2-naphtyloxy)benzoic acid was suspended in 5 ml of dried methylene chloride, to which were added 70 mg (0.55 mmol) of oxyalyl chloride and then 1 drop of DMF with a pipette. The mixture was stirred at 35° C. for 2 hours. The reaction mixture was concentrated with an evaporator, and the residue was dissolved in 5 ml of dried methylene chloride. In an atmosphere of nitrogen, the solution, while being cooled with ice, was added dropwise to a solution of 86 mg (0.5 mmol) of o-aminobenzenesulfonamide and of 2 ml of dried pyridine in dried methylene chloride (4 ml), and the resulting mixture was stirred for 4 hours in an ice bath, and then stirred overnight at room temperature. Water was added to the reaction mixture, and extracted with methylene chloride twice. The organic phase was washed with brine, dried with anhydrous sodium sulfate, and the solvent was removed by evaporation. The residue was recrystallized from a mixed solvent of isopropyl/ethyl acetate (8 ml/3 ml) to give 112 mg (54% yield) of 2-(4-(2-naphthyloxy)benzamide)benzene sulfonamide. White granular crystals.

¹ H-NMR (DMSO-d₆) δ (ppm): 7.23(d, J=8.9Hz, 2H), 7.26-7.38(m, 2H), 7.46-7.68(m, 4H), 7.90(d, J=7.9Hz, 2H), 7.97(d, J=8.6Hz, 3H), 8.04(d, J=9.2Hz, 1H), 8.46(dd, J=1.0 and 8.6Hz, 1H).

Example 77 Production of 2-(4-(2-naphtyloxy)benzamide)benzonitrile (Compound No. 1108) ##STR111##

Under an atmosphere of nitrogen, 264 mg (1.0 mmol) of 4-(2-naphtyloxy)benzoic acid was suspended in 5 ml of dried methylene chloride, to which were added 140 mg (1.1 mmol) of oxyalyl chloride and then 1 drop of DMF with a pipette. The mixture was stirred at 35° C. for 2 hours. The reaction product was concentrated with an evaporator, and the residue was dissolved in 7 ml of dried methylene chloride. In an atmosphere of nitrogen, the solution, while being cooled with ice, was added dropwise to a solution of 118 mg (1.0 mmol) of anthranilonitrile and of 111 mg (1.1 mmol) of triethyl amine in dried methylene chloride (5 ml), and the resulting mixture was stirred for 4 hours in an ice bath, and then stirred overnight at room temperature. Water was added to the reaction mixture, and extracted with methylene chloride twice. The organic phase was washed with brine, dried with anhydrous sodium sulfate, and the solvent was removed by evaporation. The residue purified by silica gel-column chromatography (hexane:ethyl acetate=20:1 to 5:1) to give 263 mg (72% yield) of 2-(4-(2-naphthyloxy)benzamide) benzonitrile. White solid.

¹ H-NMR (CDCl₃) δ (ppm): 7.15(d, J=8.9Hz, 2H), 7.18-7.30(m, 2H), 7.46-7.54(m, 3H), 7.61-7.69(m, 2H), 7.76-7.79(m, 1H), 7.85-7.96(m, 4H), 8.34(br, s, 1H), 8.61(d, J=8.6Hz, 1H).

Example 78 Production of 2-(4-(2-naphtylthio)benzamide)benzonitrile (Compound No. 3103) ##STR112##

A 280 mg (1.0 mmol) of 4-(2-naphtylthio)benzoic acid was used as a starting material. 104 mg of the title compound was prepared according to the procedure in Example 77 (yield 27%).

¹ H-NMR (CDCl₃) δ (ppm): 7.21(t, J=8.6Hz, 1H), 7.33(d, J=8.6Hz, 2H), 7.49-7.68(m, 4H), 7.78-7.89(m, 4H), 8.06(d, J=1.3Hz, 1H), 8.31(br, s, 1H), 8.59(d, J=8.6Hz, 1H).

Example 79 Production of 1-(4-(2-naphtyloxy)benzamide)-2-(tetrazol-5-yl)benzene (Compound No. 1109) ##STR113##

A 109 mg (0.30 mmol) of 2-(4-(2-naphtyloxy)benzamide)benzonitrile (Compound No. 1108), 48 mg (0.9 mmol) of ammonium chloride and 59 mg (0.9 mmol) of sodium azide were suspended in 3 ml of dried DMF, and the suspension was stirred at 80° C. for 24 hours. To the reaction mixture were added 5 ml of water and 5 ml of 5 N hydrochloric acid, and to the resulting mixture was extracted with ethyl acetate twice. The organic phase was washed with brine, dried with anhydrous sodium sulfate, and the solvent was removed by evaporation. The residue was recrystallized from 15 ml of acetonitrile to give 92 mg (75% yield) of 1-(4-(2-naphthyloxy)benzamide)-2-(tetrazol-5-yl)benzene. White needle-like crystals.

¹ H-NMR (CDCl₃) δ (ppm): 7.15-7.21(m, 2H), 7.27-7.35(m, 2H), 7.43-7.53(m, 3H), 7.57-7.63(m, 1H), 7.78-8.01(m, 4H), 8.14-8.19(m, 2H), 8.76-8.81(m, 1H).

Example 80 Production of 1-(4-(2-naphtylthio)benzamide)-2-(tetrazol-5-yl)benzene (Compound No. 3104) ##STR114##

A 50 mg (0.13 mmol) of 2-4-(2-naphtylthio)benzamide)benzonitrile (Compound No. 3103) obtained in Example 78 was used as a starting material. 43 mg of the title compound was prepared according to the procedure in Example 79 (yield 77%).

¹ H-NMR (DMSO-d₆) δ (ppm): 7.42(t, J=8.6Hz, 1H), 7.48(d, J=8.3Hz, 2H), 7.57-7.70(m, 4H), 8.00-8.09(m, 6H), 8.24(d, J=1.7Hz, 1H), 8.57(d, J=7.6Hz, 1H). 11.56(br, s, 1H).

Example 81 Production of 2-(3-amino-4-(2-naphtyloxy)benzamide)benzoic Acid Methyl Ester (Compound No. 1117) ##STR115##

A 350 mg (0.79 mmol) of 2-(4-(2-naphtyloxy)-3-nitrobenzamide)benzoic acid methyl ester (Compound No. 1114) obtained in Example 7 was dissolved in 20 ml of ethyl acetate, to which was added 97 mg of 10% Pd/C. The system was put in an atmosphere of hydrogen, and stirred at room temperature for 4 hours. The reaction mixture was filtered through a sheet of celite and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 to 2:1) to give 200 mg (61% yield) of 2-(3-amino-4-(2-naphthyloxy)benzamide)benzoic acid.

¹ H-NMR (CDCl₃) δ (ppm): 3.95(s, 3H), 6.95(d, J=8.5Hz, 1H), 7.11(t, J=7.0Hz, 1H), 7.30(dd, J=2.3 and 8.9Hz, 2H), 7.36(dd, J=2.3 and 8.2Hz, 2H), 7.40-7.50(m, 3H), 7.57(d, J=2.0Hz, 1H), 7.61(dd, J=1.4 and 8.6Hz, 1H), 7.71(d, J=7.9Hz, 1H), 7.84(t, J=8.0Hz, 2H), 8.07(dd, J=1.5 and 8.7Hz, 1H), 8.92(d, J=1.3 and 8.3Hz, 1H), 11.9(s, 1H).

Example 82 Production of 2-(3-amino-4-(2-naphtyloxy)benzamide)benzoic Acid (Compound No. 1118) ##STR116##

A 200 mg (0.48 mmol) of 2-(3-amino-4-(2-naphtyloxy)benzamide) benzoic acid methyl ester (Compound No. 1117) obtained in Example 81 was used as a starting material. 51 mg of the title compound was prepared according to the procedure in Example 2 (Yield 26%).

¹ H-NMR (DMSO-d₆) δ (ppm): 5.40(br, s, 2H), 6.96(d, J=7.8Hz, 1H), 7.10-7.30(m, 2H), 7.30-7.35(m, 2H), 7.40-7.50(m, 3H), 7.63(dt, J=1.5 and 7.6Hz, 1H), 7.82(d, J=7.8Hz, 1H), 7.90(d, J=7.8Hz, 1H), 7.96(d, J=9.8Hz, 1H), 8.05(dd, J=1.5 and 7.8Hz, 1H), 8.73(d, J=7.8Hz, 1H), 12.2(s, 1H).

Example 83 Production of the Sodium Salt of 2-(4-(2-naphtyloxy)benzamide)benzoic Acid-Ethanol Complex. (Compound No. 1104) ##STR117##

A 10.35 g (27.0 mmol) of 2-(4-(2-naphtyloxy)benzamide)benzoic acid (Compound No. 1104) obtained in Example 2 was dissolved in 250 ml of ethanol under heating, to which was added 13.77 ml (27.54 mmol) of 2 N sodium hydroxide. The resulting mixture was stirred at room temperature for 10 minutes and allowed to stand overnight. White crystallized solids were filtered to give 10.15 g (yield 83%) of the compound indicated in the title.

¹ H-NMR (DMSO-d₆) δ (ppm): 1.07(t, J=6.9Hz, 3H), 3.44-3.47(m, 2H), 4.30-4.32(m, 1H), 6.97(t, J=7.5Hz, 1H), 7.17(d, J=7.5Hz, 2H), 7.30(t, J=6.9Hz, 1H), 7.35(d, J=8.5Hz, 1H), 7.47-7.55(m, 3H), 7.87(d, J=8.0Hz, 1H), 7.94(d, J=8.0Hz, 1H), 8.02(t, J=8.0Hz, 2H), 8.09(d, J=8.5Hz, 2H), 8.69(d, J=8.0Hz, 1H), 15.66 (br, s, 1H).

Example 84 Production of the Lysine Salt of 2-(4-(2-naphtyloxy)benzamide)benzoic Acid (Compound No. 1104) ##STR118##

A 192 mg (0.5 mmol) of 2-(4-(2-naphtyloxy)benzamide)benzoic acid (Compound No. 1104) obtained in Example 2 was dissolved in ethanol (6 ml) to which was added 3 ml of methanol solution of 73 mg (0.5 mmol) of 1-lysine free base. The resulting mixture was stirred at room temperature for 5 minutes, and allowed to stand for 6 hours. White crystallized solid was filtered to give 247 mg (93% recovery) of the compound indicated in the title.

¹ H-NMR (CDCl₃ -CD₃ OD) (ppm): 1.40-1.58(m, 2H), 1.58-1.73(m, 2H), 1.78-1.90(m, 2H), 2.86-2.97(m, 2H), 3.50-3.60(m, 1H), 7.03-7.19(m, 3H), 7.23-7.32(m, 1H), 7.39-7.53(m, 4H), 7.75-7.83(m, 1H), 7.83-7.98(m, 2H), 8.05-8.17(m, 3H), 8.65-8.73(m, 1H).

Example 85 Production of the N-methyl-D-glucamine Salt of 2-(4-(2-naphtyloxy)benzamide)benzoic Acid (Compound No. 1104) ##STR119##

A 383 mg (1.0 mmol) of 2-(4-(2-naphtyloxy)benzamide)benzoic acid (Compound No. 1104) obtained in Example 2 was dissolved in ethanol (12 ml), to which was added 1 ml of aqueous solution of 195 mg (1.0 mmol) of N-methyl-D-glucamine. The resulting mixture was stirred at room temperature for 1 hour. The reaction product was filtered through a glass filter to remove a faint amount of impurities, and the filtrate concentrated. The residue (a viscid liquid) was dissolved in a mixed solvent comprising 20 ml of water and 1 ml of methanol, and the mixture was lyophilized to give 542 mg (yield 94%) of the compound indicated in the title in the form of white powder.

¹ H-NMR (DMSO-d₆) δ (ppm): 2.49-2.51(m, 5H), 2.89-3.07(m, 2H), 3.38-3.47(m, 3H), 3.57-3.61(m, 1H), 3.66-3.67(m, 1H), 3.86(br, s, 1H), 4.40-4.44(br, s, 1H), 4.58(br, s, 1H), 5.43(br, s, 1H), 6.98(t, J=8.6Hz, 1H), 7.20(d, J=8.9Hz, 2H), 7.22-7.39(m, 2H), 7.45-7.57(m, 3H), 7.87-8.09(m, 6H), 8.64(d, J=8.3Hz, 1H).

Example 86 Production of the Sodium Salt of 1-(4-(2-naphtyloxy)benzamide)-2-(tetrazol-5-yl)benzene (Compound No. 1109) ##STR120##

A 732 mg (1.80 mmol) of 1-(4-(2-naphtyloxy)benzamide)-2-(tetrazol-5-yl)benzene (Compound No. 1109) obtained in Example 79 was dissolved in 80 ml of ethanol under heating, to which was added 0.897 ml (1.80 mmol) of 2 N sodium hydroxide aqueous solution. The resulting mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated and the residue (a clear film) was dissolved in 30 ml of distilled water. The resulting solution was filtered through a filter (0.45 μm), and the filtrate was lyophilyzed to give 767 mg (yield 99%) of the compound indicated in the title in the form of white powder.

¹ H-NMR (DMSO-d₆) (ppm): 7.15(td, J=1.5 and 7.8Hz, 1H), 7.25(dt, J=2.9 and 8.8Hz, 2H), 7.31(td, J=1.5 and 8.8Hz, 1H), 7.39(dd, J=2.5 and 8.8Hz, 1H), 7.47-7.54(m, 2H), 7.60(d, J=2.4Hz, 1H), 7.90(d, J=7.8Hz, 1H), 7.90(d, J=7.8Hz, 1H), 7.96(d, J=7.8Hz, 1H), 8.03(d, J=9.3Hz, 1H), 8.25-8.30(m, 3H), 8.79(dd, J=1.0 and 8.3Hz, 1H), 13.39(br, s, 1H).

Example 87 Production of the Sodium Salt of 2-(4-(2-naphtyloxy)phenylacetamide)benzoic Acid (Compound No. 1126) ##STR121##

A 9.538 g (24.00 mmol) of 2-(4-(2-naphtyloxy)phenylacetamide)benzoic acid (Compound No. 1126) obtained in Example 13 was dissolved in 100 ml of ethanol under heating, to which was added 11.976 ml (24.00 mmol) of 2 N sodium hydroxide aqueous solution. The resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated and the residue (a clear film) was dissolved in 200 ml of distilled water. The resulting solution was filtered through a filter (0.45 μm), and the filtrate was lyophilized to give 9.97 g (yield 99%) of the compound indicated in the title in the form of white powder.

¹ H-NMR (DMSO-d₆) δ (ppm): 3.65(s, 2H), 6.95(t, J=8.2Hz, 1H), 7.10(d, J=8.6Hz, 2H), 7.25(t, J=7.3Hz, 1H), 7.33-7.36(m, 1H), 7.37-7.53(m, 5H), 7.93(t, J=7.3Hz, 2H), 7.99(d, J=8.9Hz, 2H), 8.46(d, J=8.3Hz, 1H), 14.80-14.91(m, 1H).

Example 88 Production of 2-(4-(6-hydroxy-2-naphtyloxy)benzamide)benzoic Acid Methyl Ester (Compound No. 1201) ##STR122##

A 1.35 g (2.68 mmol) of 2-(4-(6-benzyloxy-2-naphtyloxy)benzamide)benzoic acid methyl ester (Compound No. 1205) obtained in Example 22 was dissolved in 50 ml of THF, to which was added 630 mg of 10% Pd/C. The system was put in an atmosphere of hydrogen, and stirred at room temperature for 32 hours. The reaction mixture was filtered through a sheet of celite and the filtrate was concentrated to give 1.04 g (94% yield) of 2-(4-(6-hydroxy-2-naphthyloxy)benzamide)benzoic acid methyl ester.

¹ H-NMR (CDCl₃) δ (ppm): 3.88(s, 3H), 5.26(br, s, 1H), 6.90-7.20(m, 6H), 7.35(br, s, 1H), 7.50-7.70(m, 3H), 7.90-8.05 (m, 3H), 8.84(d, J=7.6Hz, 1H), 11.95(br, s, 1H).

Example 89 Production of 2-(4-(6-hydroxy-2-naphtyloxy)benzamide)benzoic Acid (Compound No. 1202) ##STR123##

A 1.04 g (2.52 mmol) of 2-(4-(6-hydroxy-2-naphtyloxy)benzamide)benzoic acid methyl ester(Compound No. 1201) obtained in Example 88 was used as a starting material. 0.78 g (yield 78%) of the title compound was prepared according to the procedure in Example 2.

¹ H-NMR (DMSO-d₆) δ (ppm): 7.05-7.20(m, 6H), 7.24(s, 1H), 7.60(dt, J=2.0 and 9.0Hz, 1H), 7.74(dd, J=9.0 and 13.0Hz, 2H), 7.95(d, J=8.9Hz, 2H), 8.03(dd, J=1.7 and 8.0Hz, 1H), 8.28(d, J=9.0Hz, 1H), 9.70(s, 1H), 12.2(br, s, 1H), 13.7(br, s, 1H).

Example 90 Production of 2-(4-(6-hydroxy-2-naphtyloxy)phenylacetiamide)bezoic Acid Methyl Ester (Compound No. 1207) ##STR124##

A 50 mg (0.097 mmol) of 2-(4-(6-benzyloxy-2-naphtyloxy)phenylacetamide)benzoic acid methyl ester(Compound No. 1223) obtained in Example 88 was used as a strong material. 22 mg of the title compound was prepared according to the procedure in Example 88 (Yield 53%).

¹ H-NMR (CDCl₃) δ (ppm): 3.76(s, 2H), 3.89(s, 3H), 5.26(br, s, 1H), 7.02-7.15(m, 5H), 7.22(dd, J=2.3 and 8.9Hz, 1H), 7.31-7.37(m, 3H), 7.53(dt, J=1.7 and 8.9Hz, 1H), 7.60(d, J=9.2Hz, 1H), 7.64(d, J=8.9Hz, 1H), 8.01(dd, J=1.7 and 8.3Hz, 1H), 8.72(d, J=8.3Hz, 1H), 11.10(br, s, 1H).

Example 91 Production of 2-(4-(6-hydroxy-2-naphtyloxy)phenylacetamide)benzoic Acid (Compound No. 1208) ##STR125##

A 22 mg (0.05 mmol) of 2-(4-(6-hydroxy-2-naphtyloxy)phenylacetamide)benzoic acid methyl ester(Compound No. 1207) obtained in Example 90 was used as a starting material. 9 mg of the title compound was prepared according to the procedure in Example 2 (Yield 42%).

¹ H-NMR (DMSO-d₆) δ (ppm): 3.83(s, 2H), 7.07-7.28(m, 6H), 7.41-7.46(m, 3H), 7.65(d, J=7.6Hz, 1H), 7.75(d, J=8.9Hz, 1H), 7.81(d, J=8.9Hz, 1H), 8.04(dd, J=1.3 and 7.9Hz, 1H), 8.59(d, J=8.3Hz, 1H) 9.72(s, 1H), 11.24(br, s, 1H), 13.65(br, s, 1H).

Example 92 In Vitro Inhibition of the Production of Human IgE Antibodies

According to the method described in J. Immunol., 146:1836-1842, 1991 and J. Immunol., 147:8-13, 1991, the concentrations of IgE and IgG antibodies were measured by the procedures described below.

Peripheral venous blood was sampled from the healthy person, and submitted to density-gradient centrifugation to isolate lymphocytes. The lymphocytes thus obtained were washed and suspended in a culture medium (RPMI-1640 (provided by Gibco)+10% heat-inactivated FCS (Whittaker)+100 g/ml streptomycin+100 U/ml penicillin+2mM L-glutamine). The cell suspensions were cultured for 1 week in the presence/absence of the compounds of this invention at the concentrations as described in Tables 3-1 to 3-2 together with human interleukin 4 (IL-4, Genzyme)(0.1 mg/ml), anti CD40 antibodies (anti CD40Ab, Biosource, clone B-B20)(2 mg/ml) and human interleukin 10 (IL-10, Genzyme)(0.2 mg/ml). The culture medium was supplied freshly to the cell suspension, and the mixture was further cultured for another week. The supernatant was sampled and the concentrations of IgE and IgG antibodies therein were measured by sandwich ELISA.

The ELISA was based, for the assay of IgE antibodies, on the use of rabbit anti-human IgE() antibodies (ICN) as the primary antibody and biotin-linked anti-human IgE monoclonal antibodies (G7-26, PharMingen) as the secondary antibody. For the assay of IgG antibodies, anti-human IgG monoclonal antibodies (G18-145, PharMingen) and biotin-linked donkey anti-human IgG antibodies (H+L)(Jackson) were used for the primary and secondary antibodies, respectively. For the assay of both IgE and IgG antibodies, Avidin-Biotin-Horse Radish Peroxidase (ABC kit, Vector Lab) and TMB (3,3',5,5'-tetramethylbenzidine) microwell peroxidase substrate system (Kirkegaard & Perry Laboratories Inc.) were used as the enzyme and the substrate, respectively. The assays were made by the use of conventionally known ELISA.

The inhibitory effect (%) of a given compound of this invention on the production of the antibody was calculated with respect to the concentration of the same antibody when the compound was not coexistent (refer to Uejima et al., American Academy of Allergy and Immunology, Proceedings of 1995 Annual Meeting, Program No. 818). The results are listed in Tables 3-1 to 3-2.

                  TABLE 3-1                                                        ______________________________________                                         Inhibitory effect of naphthalene derivatives on                                antibody production (in vitro)                                                                     Inhibition of                                                       Concentration                                                                             antibody production (%)                                    Compound No.                                                                              (μM)      IgE       IgG                                          ______________________________________                                         1101       3            30.3      -2.8                                         1104       1            35.9      -4.7                                                    3            85.6      -6.2                                                    10           98.2      20.5                                         1105       3            42.4      -6.4                                         1106       3            42.6      -25.3                                        1107       3            44.9      -17.2                                        1111       3            38.0      20.0                                         1116       3            93.0      36.9                                         1118       3            77.2      -12.9                                        1120       3            19.9      13.6                                         1122       3            59.9      9.7                                          1123       3            21.7      -0.8                                         1126       1            63.9      -5.0                                                    3            93.5      35.4                                                    10           97.9      84.0                                         1148       3            25.5      10.3                                         3102       3            19.9      -2.8                                         3103       3            41.9      3.5                                          4103       3            45.5      -4.2                                         5104       3            51.4      1.6                                          7102       3            15.4      5.4                                          8102       3            60.0      9.7                                          ______________________________________                                    

                  TABLE 3-2                                                        ______________________________________                                                             Inhibition of                                                       Concentration                                                                             antibody production (%)                                    Compound No.                                                                              (μM)      IgE       IgG                                          ______________________________________                                         1204       3            64.0      -11.4                                        1202       3            76.6      -8.7                                         1206       3            84.0      11.5                                         1224       3            78.6      83.2                                         1216       3            84.7      19.3                                         1214       3            86.1      41.6                                         1218       3            91.4      47.8                                         1210       3            92.8      59.9                                         1212       3            89.1      74.6                                         1150       3            64.4      3.3                                          1158       3            57.7      -5.2                                         1160       3            59.7      -1.3                                         1162       3            82.1      -0.3                                         1208       3            86.2      -8.4                                         1220       3            99.1      43.4                                         1222       3            98.9      36.6                                         1226       3            98.4      50.6                                         1228       3            98.9      42.4                                         ______________________________________                                    

Tables 3-1 and 3-2 show that the compounds of this invention inhibit the production of IgE antibodies.

This result suggests that the compounds of this invention would be effective as a drug for propylaxis and/or treatment of allergic diseases such as bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, anaphylactic shocks, mite allergy, pollinosis, food allergy or the like. The inhibitory activity was IgE preferential. This result suggests that the compounds of this invention would not act as an immunosuppressant based on their inhibitory effect on IgG production but would rather act as a drug more selectively prophylactic and/or therapeutic towards allergic diseases.

Example 93 Inhibitory Effects on the TF Production in Human Peripheral Blood Monocytes

Peripheral venous blood was sampled from the healthy person, and submitted to density-gradient centrifugation so that monocytes might be isolated. The monocytes thus obtained were washed with minimum essential medium (MEM, Gibco) and suspended in a culture medium (RPMI-1640(Gibco)+25 mM HEPES buffer+100 μg/ml streptomycin+100 U/ml penicillin G+2 mM L-glutamine) to give a suspension with a density of 1×10⁶ cells/ml. A 0.15 ml of the cell suspension was placed onto each of the wells of a 96-well microplate, to which the compound of this invention as described in Tables 4-1 to 4-2 was added (0.05 ml of the culture medium), and the assembly was placed for 1 hour in a CO₂ incubator for cultivation. Then, LPS (lipopolysaccarides, E. coli 0111B4, Difco) 1 μg/ml was added thereto, and the assembly was further cultured for 16 hours. After the supernatant being removed, the residue was washed with physiological saline, 0.1 ml of 16 mM OG (n-octyl-β-D-glucopyranoside) was added thereto, and the assembly was stirred to make TF soluble. A 0.2 ml of physiological saline was added to each residue (final dilution was 1.5 fold) and this preparation was used for determination of the coagulation stimulating activity (TF-like activity). The test compound had been dissolved in DMSO to give a 0.1 M solution which was diluted with the culture medium prior to use. The final concentration of DMSO was 0.01% or less.

To each well of the microplate, 50 μl of human plasma and 50 μl of the test sample prepared as above for determination of the coagulation stimulating activity, or 50 μl of standard thromboplastin (human thromboplastin, Thromborel S, Behringwerke) were added. The microplate was incubated at 37° C. for 5 minutes, to which was added 25 mM CaCl₂ (50 μl/well) containing phosphorous lipids (Platelin, Organon Teknica) at a concentration of 100 μl/ml to initiate coagulation. Coagulation was determined on the basis of absorption at 540 nm, and the measurement lasted 7 to 20 minutes. The data were analyzed with a data analyzing software SOFTMax (Molecular Devices) and the maximum rate time was taken as the coagulation time. The logarithmic values of the coagulation times and standard thromboplastin concentrations are plotted, and a regression parabola was drawn among the dots to give a test curve. From the curve, the inhibitory effect (%) of a given test compound on TF production was calculated. (Refer to J. Imnmunol. Methods, 133:21-29, 1990, and Proc. Natl. Acad. Sci. USA, 89:10370-10374, 1992).

The results are shown in Tables 4-1 to 4-2.

                  TABLE 4-1                                                        ______________________________________                                         Inhibitory effect of naphthalene derivatives on TF production                  by monocytes in human peripheral blood                                                      Concentration                                                                             Inhibition of                                          Compound No. (μM)    TF production (%)                                      ______________________________________                                         1104         1          45.3                                                                3          90.4                                                                10         100.0                                                  3102         3          100.0                                                  4103         1          16.5                                                                3          74.4                                                                10         100.0                                                  7102         3          10.6                                                                10         81.1                                                   5102         1          19.8                                                                3          74.1                                                                10         99.9                                                   6102         3          75.8                                                                10         100.0                                                  1148         3          92.9                                                   1109         1          74.9                                                                3          99.4                                                                10         99.7                                                   1111         1          -9.0                                                                3          96.2                                                                10         100.0                                                  1113         1          25.3                                                                3          83.6                                                                10         100.0                                                  ______________________________________                                    

                  TABLE 4-2                                                        ______________________________________                                                      Concentration                                                                             Inhibition of                                          Compound No. (μM)    TF production (%)                                      ______________________________________                                         1116         3          96.6                                                   1118         3          86.9                                                   1126         3          26.5                                                   1146         3          23.5                                                   1202         3          33.4                                                   1204         1          75.7                                                                3          100.0                                                               10         100.0                                                  3103         3          77.9                                                   3104         3          96.9                                                   ______________________________________                                    

Tables 4-1 to 4-2 reveals that the compounds of this invention inhibit the TF production.

This result suggests that the compounds of this invention would be effective as a drug for prophylaxis and/or treatment of the diseases that are associated with enhanced production or activity of TF such as infections, delayed immune response, autoimmune diseases like SLE, rejection reactions associated with transplantation of various organs, glomerular nephritis, various thromboses associated with viral hepatitis or the like, occlusive arteriosclerosis, cerebral embolism, cerebral infarction, pulmonary embolism, pulmonary infarction, angina pectoris, myocardial infarction, restenosis, Buerger disease, diseases involved in hypertrophic endometritis, and turbidity of an artificial crystalline lens embedded for the treatment of cataract.

Example 94 In Vivo Inhibition of Mice IgG Production

TNP-KLH (trinitrophenyl-keyhole-lymphet-hemocyanin) was prepared by the method as described in J. Immunol., 97:421-430, 1966 from KLH and trinitrobenzene sulfonic acid. A 0.5 g of TNP-KLH suspended in 0.2 ml of saline and 1 mg of aluminum hydroxide gel were injected into the peritoneal cavity of BDF1 mice (8 weeks old) for immunization. From the day of immunization onward, the compound of this invention listed in Table 5 was given subcutaneously to the same animal twice a day for 10 days (100 mg/kg/day, dissolved in 0.5% Tween 80 in saline, and N=10). To the control group, 0.5% Tween 80 in saline was given at the same time schedule (N=10). Ten days after immunization, blood was extracted from the heart, and the concentrations of IgE, IgG₁ and IgM antibodies were determined by ELISA (Immunol. Lett., 23:251-256, 1990, and Eur. J. Immunol., 20:2499-2503, 1990). Inhibition (%) of the antibody production with respect to the control was calculated. The results are listed in Table 5.

                  TABLE 5                                                          ______________________________________                                         Inhibitory effect of naphthalene derivatives on                                antibody production (in vivo)                                                            Inhibition of antibody production (%)                                Compound No.                                                                               IgE          IgG.sub.1                                                                             IgM                                            ______________________________________                                         1104        60.4         24.4   56.1                                           1126        78.9         46.8   70.2                                           ______________________________________                                    

Table 5 reveals that the compounds of this invention have an in vivo strong inhibitory effect on the antibody production towards IgE, IgM and IgG₁ in this order.

This result suggests that the compounds of this invention would be effective as a drug for prophylaxis and/or treatment of allergic diseases such as bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, anaphylactic shocks, mite allergy, pollinosis, food allergy, urticaria, ulcerative colitis, eosinophilic gastroenteritis or the like.

Example 95 Inhibition of Histamine Release from Rat Mast Cells

A 1 ml of anti-DNP-Ascaris (Didets) anti-serum (prepared as described in J. Immunol., 106:1002, 1971) was injected into the peritoneal cavity of 5 SD strain rats of 7 weeks old. Forty eight hours later, the animals were bled to death, and 20 ml of HBSS (Hanks balanced salt solution) was injected into their peritoneal cavity. After about 90 second massaging, the HBSS washing was recovered, and cells released into the peritoneal cavity were collected from the washing. The ascitic cells thus collected were washed once with 0.1% BSA/Tyrode-HEPES, and then resuspended in 0.1% BSA/Tyrode-HEPES to give a suspension with a density of 5×10⁶ cells/ml. The cell suspension was incubated at 37° C. for 10 minutes in the presence/absence of a test substance, that is, the compound listed in Table 6.

To the resulting mixture was added a histamine releasing agent (20 μg/ml of DNP-Ascaris (DNP-As) (Didets)+25 μg/ml of phosphatidylserine (PS) or 0.2 μg/ml of calcium ionophore A23187), and the reaction was allowed to proceed at 37° C. for 20 minutes. Then, the cell suspension was centrifuged to obtain supernatant. Histamine released in the supernatant was determined by the fluorescent method (J. Pharmacol. Exp. Ther. 127:182, 1959). Inhibitory effect (%) of a given compound of this invention on histamine release was calculated relative to the histamine release when the compound was not coexistent. The results are shown in Table 6.

                  TABLE 6                                                          ______________________________________                                         Inhibitory effect of naphthalene derivatives on histamine                      release from mast cells of the rat                                             Histamine release                                                                        Compound  Concentration                                                                             Inhibiton of                                    agent     No.       (μM)    histamine release (%)                           ______________________________________                                         DNP-As + PS                                                                              1104       10        42.7                                                                100        84.2                                                      1126       10        25.4                                                                100        90.2                                            Δ23187                                                                             1104       10        75.4                                                                100        78.0                                                      1126       10        54.2                                                                100        79.8                                            ______________________________________                                    

Table 6 reveals that the compounds of this invention inhibit histamine release from rat mast cells.

This result suggests that the compounds of this invention would be effective as a drug for prophylaxis and/or treatment of allergic diseases such as bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, anaphylactic shocks, mite allergy, pollinosis, food allergy, urticaria, ulceative colitis, eosinophilic gastroenteritis or the like.

Example 96 Inhibition of Histamine Release from Human Basophils

To human heparinized peripheral blood was added 1/10 volume of 6% Dextran 500 in saline, and the mixture was allowed to stand at room temperature for 1 hour, to isolate a plasma layer containing leukocytes. The leukocytes were separated by centrifugation, washed with PIPE-A (119 mM NaCl, 5 mM KCl, 25 mM PIPES, 40 mM NaOH, 5.6 mM glucose, and 0.03% human serum albumin), and suspended in PIPES-ACM (PIPES A, 1 mM CaCl₂ and 0.4 mM MgCl₂) to give a cell suspension of a density of 4×10⁶ cells /ml. To this cell suspension was added the compound of this invention listed in Table 7 as a test drug (0.1 M solution of the compound in DMSO was diluted with PIPES-ACM to give a 10 M solution), or the cell suspension was left untouched. After 30 second, calcium ionophore A23187 (0.2 g/ml) was added. The reaction was allowed to proceed at 37 for 45 minutes. The resulting mixture was centrifuged to isolate a supernatant. Histamine release in the supernatant was determined by the fluorescent method. Inhibitory effect (%) of a given compound of this invention on histamine release was calculated relative to the histamine release when the compound was not coexistent(refer to Allergy, 37:313-321, 1988). The results are shown in Table 7.

                  TABLE 7                                                          ______________________________________                                         Inhibitory effect of naphthalene derivatives on                                histamine release from human basophils                                                       Inhibition of                                                    Compound No.  histamine release (%)                                            ______________________________________                                         1104          20.4                                                             1126          55.8                                                             ______________________________________                                    

Table 7 reveals that the compounds of this invention inhibit histamine release from human basophils.

This result suggests that the compounds of this invention would be effective as a drug for prophylaxis and/or treatment of allergic diseases such as urticaria, ulcerative colitis, eosinophilic colitis, bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, anaphylactic shocks, mite allergy, pollinosis, food allergy, or the like.

Example 97 Inhibition of Leukotrien B₄ (LTB₄) Production

The basophils from rats of RBL-1 line (Dainippon Pharmaceutical Co.) cultured on DMEM (Dulbecco's modified Eagle medium) containing 10% FCS suspended in 10 mM HEPES-NaOH buffer (pH 7.4), 90 mM NaCl, 3.7 mM KCl, 0.9 mM CaCl₂, 5.6mM glucose, and the compound of this invention listed in Table 8 as a test drug, to give a suspension of a density of 2×10⁶ cells/ml. The suspension was allowed to stand at 37 for 5 minutes, and calcium ionophores A23187 were added thereto in such a manner that the concentration of 5 M was obtained in the end. The reaction was allowed to proceed at 37 for 10 minutes, and the supernatant was sampled for the ELISA assay (Cayman Chemical, Catalog No. 520111, and J. Immunol., 119:618-622, 1977) of leukotrien B₄ (LTB₄). IC50 of a given compound of this invention for inhibition of leukotrien production was calculated relative to the production of LTB₄ when the compound was not coexistent.

The results are shown in Table 8.

                  TABLE 8                                                          ______________________________________                                         Inhibitory effect of naphthalene derivatives on leukotrien                     B.sub.4 (LTB.sub.4) production                                                 Compound No.   IC.sub.50 (μM)                                               ______________________________________                                         1104           0.21                                                            1126           0.60                                                            ______________________________________                                    

Table 8 reveals that the compounds of this invention inhibit the LTB₄ production. This result suggests that the compounds of this invention would be effective as a drug for prophylaxis and/or treatment of allergic diseases such as urticaria, ulcerative colitis, eosinophilic gastroenteritis, bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, anaphylactic shocks, mite allergy, pollinosis, food allergy, or the like.

Furthermore, Examples 92 and 94-97 demonstrated that the compounds of this invention have an inhibitory effect on IgE production, histamine release and LTB₄ production, suggesting that they would be effective as a drug for prophylaxis and/or treatment of allergic diseases not only because of their inhibitory action on IgE production, but also because of their suppressing effects on chemical mediators, such as histamine and LTB₄.

Example 98 Preparation of Tablets

From the compounds of this invention were made tablets each of which contains the following as ingredients.

    ______________________________________                                         Compound No. 1104                                                                               50           mg                                               Lactose          230          mg                                               Potato starch    80           mg                                               Polyvinylpyrrolidone                                                                            11           mg                                               Magnesium stearate                                                                              5            mg                                               ______________________________________                                    

The compound of this invention (Compound No. 1104), lactose and potato starch were mixed, and wetted evenly with 20% solution of polyvinylpyrrolidone in ethanol. The resulting mass was strained with a 20 nm mesh, dried at 45° C., and strained again with a 15 nm mesh. The granules thus obtained were mixed with magnesium stearate, and compacted into tablets.

FIELD OF INDUSTRIAL UTILITY

This invention provides naphthalene derivatives capable of, for example, inhibiting the production of IgE antibodies and of TF. Inhibitory activity on IgE production is especially attractive in view of IgE selectivity, potency, and low toxicity. Accordingly, the compounds of this invention would be effective for prophylaxis and treatment of allergic diseases involved in the augmented production of IgE antibodies such as certain bronchial asthma, conjunctivitis, rhinitis, dermatitis, hypersensitivity or the like, and of the diseases resulting from the augmented production/activity of TF. 

We claim:
 1. A naphthalene derivative having the following formula (I): ##STR126## wherein A represents a hydrogen atom, a hydroxy group, a C₇ -C₁₁ aralkyloxy group, or an alkoxy group composed of an oxy group and a C₁ -C₁₂ aliphatic or alicyclic, saturated or unsaturated hydrocarbon group in which the alkyl moiety may be substituted with a C₆ -C₁₀ aryloxy group;O represents O, S, O--CH₂, S--CH₂, or CHOR¹ ; L represents CO, CR² R³ CO, CH₂ CH₂ CO, or CH═CHCO; D represents a hydrogen atom, NO₂, NH₂, CO₂ R⁴, or a group having the following formula (II): ##STR127## wherein G represents a hydrogen atom, OH, SO₂ NH₂, CO₂ R⁶, CN or a tetrazol-5-yl group; E represents a hydrogen atom, OH, SO₂ NH₂, CO₂ R⁵, CN, or a tetrazol-5-yl group; M represents a hydrogen atom, a C₁ -C₄ lower alkyl group, a nitro group, or a halogen atom; and R¹, R², R³, R⁴, R⁵ and R⁶, independently represent a hydrogen atom or a C₁ -C₄ lower alkyl group; a pharmacologically acceptable salt thereof or a pharmacologically acceptable solvate thereof.
 2. The naphthalene derivative according to claim 1 wherein E represents CO₂ R⁵ where R⁵ represents a hydrogen atom or a C₁ -C₄ lower alkyl group or a tetrazol-5-yl group, the pharmacologically acceptable salt or the pharmacologically acceptable solvate thereof.
 3. The naphthalene derivative according to claim 1 wherein D represents a hydrogen atom, NO₂, NH₂ or a group represented by formula (II) wherein G represents a hydrogen atom or CO₂ R⁶, and R⁶ represents a hydrogen atom or a C₁ -C₄ lower alkyl group, the pharmacologically acceptable salt thereof or the pharmacologically acceptable solvate thereof.
 4. The naphthalene derivative according to claim 1, wherein D represents a hydrogen atom or NO₂, E represents CO₂ R⁵, and R⁵ represents a hydrogen atom or a C₁ -C₄ lower alkyl group, the pharmacologically acceptable salt or the pharmacologically acceptable solvate thereof.
 5. The naphthalene derivatives according to claim 1 wherein M is a hydrogen atom, a methyl group, an ethyl group, a nitro group, a fluorine atom or a chlorine atom, the pharmacologically acceptable salt or the pharmacologically acceptable solvate thereof.
 6. The naphthalene derivatives according to claim 1, wherein R¹ -R⁶ represent, independently a hydrogen atom or a methyl group, the pharmacologically acceptable salt or the pharmacologically acceptable solvate thereof.
 7. The naphthalene derivative according to any one claim of claims 1-6, wherein O represents O, S, O--CH₂, S--CH₂, or CHOR¹ where R¹ represents a hydrogen atom or a C₁ -C₄ lower alkyl group and L represents CO, CR² R³ CO or CH═CHCO where R² and R³, independently represent a hydrogen atom or a C₁ -C₄ lower alkyl group, the pharmacologically acceptable salt or the pharmacologically acceptable solvate thereof.
 8. The naphthalene derivative according to any one claim of claims 1-6, wherein O represents O, S, or CHOR¹ where R¹ represents a hydrogen atom or a C₁ -C₄ lower alkyl group and L represents CO or CR² R³ CO where R² and R³, independently represent a hydrogen atom or a C₁ -C₄ lower alkyl group, the pharmacologically acceptable salt or the pharmacologically acceptable solvate thereof.
 9. The naphthalene derivative according to any one claim of claims 1-6, wherein O represents O and L represents CO or CR² R³ CO where R² and R³, independently are a hydrogen atom or a C₁ -C₄ lower alkyl group, the pharmacologically acceptable salt or the pharmacologically acceptable solvate thereof.
 10. The naphthalene derivative according to any one claim of claims 1-6, wherein O represents O, S, O--CH₂ or S--CH₂ and L represents CO or CH═CHCO, the pharmacologically acceptable salt or the pharmacologically acceptable solvate thereof.
 11. The naphthalene derivative according to any one claim of claims 1-6, wherein O represents O, S, O--CH₂ or S--CH₂, and L represents CO, the pharmacologically acceptable salt or the pharmacologically acceptable solvate thereof.
 12. The naphthalene derivatives according to any one claim of claims 1-6, wherein O represents O, and L represents CH═CHCO, the pharmacologically acceptable salt or the pharmacologically acceptable solvate thereof.
 13. The naphthalene derivatives according to claim 1, wherein A represents a hydrogen atom; a hydroxy group; an alkoxy group composed of an oxy group and a C₁ -C₁₂ aliphatic or alicyclic, a saturated hydrocarbon group or a C₃ -C₁₀ aliphatic unsaturated hydrocarbon group, which can be substituted by a phenyloxy group; a benzyloxy group; a phenylpropyloxy group; or a naphtylmethyloxy group, the pharmacologically acceptable salt or the pharmacologically acceptable solvate thereof.
 14. The naphthalene derivative according to any one claim of claims 1-12, wherein the substitution by O on the naphthalene ring is at the 2-position of the ring, the pharmacologically acceptable salt or the pharmacologically acceptable solvate thereof.
 15. The naphthalene derivative according to any one claim of claims 1-12, wherein substitution by O, L and D are on the benzene ring and the relative position of O and L is para, the pharmacologically acceptable salt or the pharmacologically acceptable solvate thereof.
 16. A pharmaceutical composition comprising the naphthalene derivatives as described in claim 1, the pharmacologically acceptable salt or the pharmacologically acceptable solvate thereof and a pharmaceutically acceptable carrier.
 17. The pharmaceutical composition according to claim 16, wherein the pharmaceutical composition is as a drug for treating an allergic disease based on an inhibitory action on the production of IgE antibodies.
 18. The pharmaceutical composition according to claim 17, wherein the allergic disease is bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, anaphylactic shocks, mite allergy, pollinosis or food allergy.
 19. The pharmaceutical composition according to claim 16, wherein the pharmaceutical composition is effective for the treatment of disease caused by augmented production or activity of TF.
 20. The pharmaceutical composition according to claim 19, wherein the disease is DIC; thrombosis; occlusive arteriosclerosis; cerebral embolism; cerebral infarction; pulmonary embolism; pulmonary infarction; angina pectoris; myocardial infarction; restenosis; Buerger disease; diseases involved in hypertrophic endometritis; and turbidity of an artificial crystalline lens embedded for the treatment of cataract.
 21. A medicine effective as a prophylactic and/or therapeutic for an allergic disease because of its inhibitory effect on the production of IgE antibody containing a napththalene derivative of claim 1, the pharmacologically acceptable salt or the pharmacologically acceptable solvate as an active ingredient(s).
 22. The medicine effective as a prophylactic and/or therapeutic for an allergic disease according to claim 21 being more selectively inhibitory against the production of IgE antibody than against IgG antibody.
 23. The medicine effective as a prophylactic and/or therapeutic for a disease resulting from enhanced production or activity of TF containing a naphthalene derivative of claim 1, the pharmacologically acceptable salt or the pharmacologically acceptable solvate as an active ingredient(s).
 24. A naphthalene derivative having the following formula (I): ##STR128## wherein A represents a hydroxy group, a C₇ -C₁₁, aralkyloxy group, or an alkoxy group composed of an oxy group and a C₁ -C₁₂ aliphatic or alicyclic, saturated or unsaturated hydrocarbon group which the alkyl moiety may be substituted with a C₆ -C₁₀ aryloxy group;Q represents O, S, O--CH₂, S--CH₂, or CHOR₁ ; L represents CO, CR² R³ CO, CH₂ CH₂ CO, or CH═CHCO; D represents a hydrogen atom, NO₂, NH₂, CO₂ R⁴, or a group having the following formula (II): ##STR129## wherein G represents a hydrogen atom, OH, SO₂ NH₂, CO₂ R⁶, CN or a tetrazol-5-yl group; E represents a hydrogen atom, OH, SO₂ NH₂, CO₂ R⁵, CN, or a tetrazol-5-yl group; M represents a hydrogen atom, a C₁ -C₄ lower alkyl group, a nitro group, or a halogen atom; and R¹, R², R³, R⁴, R⁵ and R⁶, independently represent a hydrogen atom or a C₁ -C₄ lower alkyl group; a pharmacologically acceptable salt thereof or a pharmacologically acceptable solvate thereof. 